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Sample records for chagosensis leucettidae founder

  1. Deep genetic divergences among Indo-Pacific populations of the coral reef sponge Leucetta chagosensis (Leucettidae): Founder effects, vicariance, or both?

    PubMed Central

    2008-01-01

    Background An increasing number of studies demonstrate that genetic differentiation and speciation in the sea occur over much smaller spatial scales than previously appreciated given the wide distribution range of many morphologically defined coral reef invertebrate species and the presumed dispersal-enhancing qualities of ocean currents. However, knowledge about the processes that lead to population divergence and speciation is often lacking despite being essential for the understanding, conservation, and management of marine biodiversity. Sponges, a highly diverse, ecologically and economically important reef-invertebrate taxon, exhibit spatial trends in the Indo-West Pacific that are not universally reflected in other marine phyla. So far, however, processes generating those unexpected patterns are not understood. Results We unraveled the phylogeographic structure of the widespread Indo-Pacific coral reef sponge Leucetta chagosensis across its known geographic range using two nuclear markers: the rDNA internal transcribed spacers (ITS 1&2) and a fragment of the 28S gene, as well as the second intron of the ATP synthetase beta subunit-gene (ATPSb-iII). This enabled the detection of several deeply divergent clades congruent over both loci, one containing specimens from the Indian Ocean (Red Sea and Maldives), another one from the Philippines, and two other large and substructured NW Pacific and SW Pacific clades with an area of overlap in the Great Barrier Reef/Coral Sea. Reciprocally monophyletic populations were observed from the Philippines, Red Sea, Maldives, Japan, Samoa, and Polynesia, demonstrating long-standing isolation. Populations along the South Equatorial Current in the south-western Pacific showed isolation-by-distance effects. Overall, the results pointed towards stepping-stone dispersal with some putative long-distance exchange, consistent with expectations from low dispersal capabilities. Conclusion We argue that both founder and vicariance events

  2. Founder of cosmonautics

    NASA Astrophysics Data System (ADS)

    Maksimov, A. I.

    2007-09-01

    The paper described the creative path of K.E. Tsiolkovsky, the founder of theoretical cosmonautics, who devoted his life to solving various problems in the field of aerodynamics and rocket engineering, creating dirigibles with a metallic shell, jet planes, and air-cushioned trains, and studying the origin of planets, the Sun, and the Universe. The main engineering proposals of a scientist of great originality, which found applications in modern rocket and space engineering, are briefly analysed. The versatility of his interests is demonstrated; his research is shown to deal with many fields of science and technology, including the kinetic theory of gases, geology, cosmology, biology, philosophy, sociology, theology, and language science.

  3. Founder effect: assessment of variation in genetic contributions among founders.

    PubMed

    O'Brien, E; Kerber, R A; Jorde, L B; Rogers, A R

    1994-04-01

    We present a Monte Carlo method for determining the distribution of founders' genetic contributions to descendant cohorts. The simulation of genes through known pedigrees generates the probability distributions of contributed genes in recent cohorts of descendants, their means, and their variances. Genealogical data from three populations are analyzed: the Hutterite population of North America, the island population of Sottunga from the Aland archipelago, and the large Utah Mormon population. Two applications of the Monte Carlo method are presented. First we investigate the relative opportunity for founder effect in the three populations, which have dissimilar pedigree structures and dissimilar disease gene frequencies. Second, we measure the reproductive success of population founders in terms of the number of genes they contribute to a cohort some number of generations descendant and compare the effects of polygyny versus monogamy on reproductive success. The distribution of Hutterite founder contributions describes the context for a classic founder effect. Hutterite founders have a higher probability of leaving no genes in the population (72%) than Sottunga (48%) and Mormon (48%) founders. However, founder genes that survive among Hutterite descendants do so in larger numbers on average than founder genes in the other two populations. Greater variation among monogamous Hutterite founders compared with Mormon polygynous founders demonstrates that polygyny alone does not maximize the variance in reproductive success; other population characteristics are at least as important for determining variability among individuals in their genetic contributions to a gene pool. Our findings make it difficult to appreciate the reproductive advantage of polygyny in the Mormon population. Although the expected gene contributions and their variances were larger for polygynous founders compared with other Mormons, the main effect of polygyny was to increase the probability that

  4. [Founder mutation in Lynch syndrome].

    PubMed

    Cajal, Andrea R; Piñero, Tamara A; Verzura, Alicia; Santino, Juan Pablo; Solano, Angela R; Kalfayan, Pablo G; Ferro, Alejandra; Vaccaro, Carlos

    2016-01-01

    Lynch syndrome is the most frequent syndrome in hereditary colorectal cancer, a family-specific deleterious mutations in genes encoding DNA reparation proteins: MLH1 (mutL homolog 1), MSH2, MSH6 (mutS homolog 2 y 6, respectively), PMS2 (PMS1 homolog 2, mismatch repair system component) y MUTYH (mutY DNA glycosylase). The c.2252_2253delAA, p.Lys751Serfs*3 mutation in MLH1 gene segregates with a haplotype reported in the northern region of Italy and whose origin was attributed to a founder effect. This mutation co-segregates with typical characteristics of Lynch syndrome, including early age at onset and multiple primary tumors in the same individual, a high frequency of pancreatic cancer, high microsatellite instability and lack of PMS2 expression. This report describes a mutation in an Argentinian patient with endometrioid adenocarcinoma of uterus. Her first-degree relatives had a history of colon cancer diagnosed before 50 years, fulfilling the Amsterdam Criteria I and Lynch syndrome II. The high pathogenicity associated to this mutation makes necessary the study of all members from families with hereditary cancer, allowing pre-symptomatic genetic diagnosis, early assessment and the instauration of preventive treatments. PMID:27295708

  5. Moving Forward with Founders: Strategies for Change in Volunteer Organizations

    ERIC Educational Resources Information Center

    Huff, Paula Rogers; Pleskac, Sue

    2012-01-01

    Founder's Syndrome can create barriers to change in Extension programs. As a result, Extension staff have experienced challenges in effecting organizational change where Founders are present. 4-H Youth Development staff in Wisconsin applied a variety of strategies to move forward with 4-H programming, despite the influence of the Founders.…

  6. Variation in founder groups promotes establishment success in the wild.

    PubMed

    Forsman, Anders; Wennersten, Lena; Karlsson, Magnus; Caesar, Sofia

    2012-07-22

    Environmental changes currently pose severe threats to biodiversity, and reintroductions and translocations are increasingly used to protect declining populations and species from extinction. Theory predicts that establishment success should be higher for more variable groups of dissimilar individuals. To test this 'diversity promotes establishment' hypothesis, we introduced colour polymorphic pygmy grasshoppers (Tetrix subulata) to different sites in the wild. The number of descendants found at the release sites the subsequent year increased with increasing number of colour morphs in the founder group, and variation in founder groups also positively affected colour morph diversity in the established populations. Since colour morphs differ in morphology, physiology, behaviour, reproductive life history and types of niche used, these findings demonstrate that variation among individuals in functionally important traits promotes establishment success under natural conditions, and further indicate that founder diversity may contribute to evolutionary rescue and increased population persistence. PMID:22456885

  7. Utilization of founder lines for improved Citrus biotechnology via RMCE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    On October 1st 2011 the CRB chose to fund a unique research project, the development of citrus cultivars specifically for genetic engineering (GE). The objective of this research was to develop GE citrus ‘Founder Lines’ containing DNA sequences that will allow the precise insertion of genes for de...

  8. Beringian Standstill and Spread of Native American Founders

    PubMed Central

    Tamm, Erika; Kivisild, Toomas; Reidla, Maere; Metspalu, Mait; Smith, David Glenn; Mulligan, Connie J.; Bravi, Claudio M.; Rickards, Olga; Martinez-Labarga, Cristina; Khusnutdinova, Elsa K.; Fedorova, Sardana A.; Golubenko, Maria V.; Stepanov, Vadim A.; Gubina, Marina A.; Zhadanov, Sergey I.; Ossipova, Ludmila P.; Damba, Larisa; Voevoda, Mikhail I.; Dipierri, Jose E.; Villems, Richard; Malhi, Ripan S.

    2007-01-01

    Native Americans derive from a small number of Asian founders who likely arrived to the Americas via Beringia. However, additional details about the intial colonization of the Americas remain unclear. To investigate the pioneering phase in the Americas we analyzed a total of 623 complete mtDNAs from the Americas and Asia, including 20 new complete mtDNAs from the Americas and seven from Asia. This sequence data was used to direct high-resolution genotyping from 20 American and 26 Asian populations. Here we describe more genetic diversity within the founder population than was previously reported. The newly resolved phylogenetic structure suggests that ancestors of Native Americans paused when they reached Beringia, during which time New World founder lineages differentiated from their Asian sister-clades. This pause in movement was followed by a swift migration southward that distributed the founder types all the way to South America. The data also suggest more recent bi-directional gene flow between Siberia and the North American Arctic. PMID:17786201

  9. Genetic Studies of Stuttering in a Founder Population

    ERIC Educational Resources Information Center

    Wittke-Thompson, Jacqueline K.; Ambrose, Nicoline; Yairi, Ehud; Roe, Cheryl; Cook, Edwin H.; Ober, Carole; Cox, Nancy J.

    2007-01-01

    Genome-wide linkage and association analyses were conducted to identify genetic determinants of stuttering in a founder population in which 48 individuals affected with stuttering are connected in a single 232-person genealogy. A novel approach was devised to account for all necessary relationships to enable multipoint linkage analysis. Regions…

  10. Founders' Continuing Roles in Schools Supporting Self-Directed Learning

    ERIC Educational Resources Information Center

    Nash, Carol

    2014-01-01

    What should be the continuing role of founders in schools supporting self-directed learning? To answer this, the founders' views of two North American schools for self-directed learners will be compared. One school is exam-focused and private; the other is, test-free and public. The founders of both schools have comparable beliefs regarding…

  11. A newly discovered founder population: the Roma/Gypsies.

    PubMed

    Kalaydjieva, Luba; Morar, Bharti; Chaix, Raphaelle; Tang, Hua

    2005-10-01

    The Gypsies (a misnomer, derived from an early legend about Egyptian origins) defy the conventional definition of a population: they have no nation-state, speak different languages, belong to many religions and comprise a mosaic of socially and culturally divergent groups separated by strict rules of endogamy. Referred to as "the invisible minority", the Gypsies have for centuries been ignored by Western medicine, and their genetic heritage has only recently attracted attention. Common origins from a small group of ancestors characterise the 8-10 million European Gypsies as an unusual trans-national founder population, whose exodus from India played the role of a profound demographic bottleneck. Social and economic pressures within Europe led to gradual fragmentation, generating multiple genetically differentiated subisolates. The string of population bottlenecks and founder effects have shaped a unique genetic profile, whose potential for genetic research can be met only by study designs that acknowledge cultural tradition and self-identity. PMID:16163730

  12. Of Founder Populations, Long QT Syndrome, and Destiny

    PubMed Central

    Schwartz, Peter J.; Brink, Paul A.

    2009-01-01

    Founder populations, characterized by a single ancestor affected by LQTS and by a large number of individuals and families all related to the ancestor and thereby carrying the same disease-causing mutation, represent the ideal human model to study the role of “modifier genes” in the long QT syndrome (LQTS). This chapter reviews some of the fundamental concepts related to founder populations and provides the necessary historic background to understand why so many can be found in South Africa. The focus then moves onto a specific LQT1 founder population, carrier of the A341V mutation, that has been extensively studied during the last 10 years and has provided a significant number of previously unforeseen information. These novel findings range from an unusually high clinical severity not explained by the electrophysiological characteristics of the mutation, to the importance of the tonic and reflex control of heart rate for risk stratification, to the identification of the first modifier genes for the clinical severity of LQTS. PMID:19880070

  13. Native American admixture in the Quebec founder population.

    PubMed

    Moreau, Claudia; Lefebvre, Jean-François; Jomphe, Michèle; Bhérer, Claude; Ruiz-Linares, Andres; Vézina, Hélène; Roy-Gagnon, Marie-Hélène; Labuda, Damian

    2013-01-01

    For years, studies of founder populations and genetic isolates represented the mainstream of genetic mapping in the effort to target genetic defects causing Mendelian disorders. The genetic homogeneity of such populations as well as relatively homogeneous environmental exposures were also seen as primary advantages in studies of genetic susceptibility loci that underlie complex diseases. European colonization of the St-Lawrence Valley by a small number of settlers, mainly from France, resulted in a founder effect reflected by the appearance of a number of population-specific disease-causing mutations in Quebec. The purported genetic homogeneity of this population was recently challenged by genealogical and genetic analyses. We studied one of the contributing factors to genetic heterogeneity, early Native American admixture that was never investigated in this population before. Consistent admixture estimates, in the order of one per cent, were obtained from genome-wide autosomal data using the ADMIXTURE and HAPMIX software, as well as with the fastIBD software evaluating the degree of the identity-by-descent between Quebec individuals and Native American populations. These genomic results correlated well with the genealogical estimates. Correlations are imperfect most likely because of incomplete records of Native founders' origin in genealogical data. Although the overall degree of admixture is modest, it contributed to the enrichment of the population diversity and to its demographic stratification. Because admixture greatly varies among regions of Quebec and among individuals, it could have significantly affected the homogeneity of the population, which is of importance in mapping studies, especially when rare genetic susceptibility variants are in play. PMID:23776491

  14. Uplift of the Colorado Plateau via Lower Crustal Foundering

    NASA Astrophysics Data System (ADS)

    Erdman, M.; Lee, C. T.; Jiang, H.

    2014-12-01

    How the Colorado Plateau reached its current elevation with little internal deformation compared to surrounding regions has perplexed researchers for nearly a century. Hypotheses to explain the two kilometers of uplift since the Late Cretaceous range from delamination of the Farallon plate following flat slab subduction, thermal expansion of upwelling mantle, dynamic topography in response to mantle upwelling, mid-crustal flow from over-thickened crust, and foundering of a dense lower crustal root. Many of these hypotheses are constrained by geodynamic modelling with limited evidence from the rock record. We report here the petrologic and geochemical makeup of lower crustal xenoliths from the Transition Zone in Arizona between the southern Basin and Range Province and the Colorado Plateau. This xenolith suite erupted within a ~25 Ma volcanic host and is dominated by garnet pyroxenite with minor gabbro and amphibolite. Major and trace element geochemistry, petrography, and thermobarometry suggest these rocks represent deep-seated (12-25 kb) cumulates formed during arc magmatism. A preliminary U-Pb sphene age of ~50 Ma suggests that the cumulates formed during the end of the Laramide orogeny. Calculated compositional densities for these cumulates are up to 10% greater than the mantle, suggesting that early to mid-Tertiary arc magmatism generated a dense and unstable lower crustal root. Because these rocks are cold (580-840 °C), thermal contraction may further increase the density contrast. Foundering of this dense root could cause significant uplift. Isostatic calculations show that two kilometers of uplift may be explained by removal of a 20-km-thick root that is 10% denser than the underlying mantle. If lower crustal foundering is indeed responsible for uplift of the Colorado Plateau, the eruption age of the xenolith suite constrains uplift to be younger than ~25 Ma.

  15. Earth Day Then and Now: Reflections by its founder

    SciTech Connect

    Nelson, G.

    1990-04-01

    In this address, the founder of Earth Day recalls the environmental issues of twenty years ago compared to those of this year's observance. He suggests that the two superpowers cut defense spending by 50% this decade and 50% in the next decade, using some of the savings to reverse and restore global environmental damage. He also suggests that the world, and especially the United States, must reduce its reliance on oil and develop solar and other renewable energy technologies. Finally, it was emphasized that waste disposal habits must be changed.

  16. HIV-1 infections with multiple founders are associated with higher viral loads than infections with single founders.

    PubMed

    Janes, Holly; Herbeck, Joshua T; Tovanabutra, Sodsai; Thomas, Rasmi; Frahm, Nicole; Duerr, Ann; Hural, John; Corey, Lawrence; Self, Steve G; Buchbinder, Susan P; McElrath, M Juliana; O'Connell, Robert J; Paris, Robert M; Rerks-Ngarm, Supachai; Nitayaphan, Sorachai; Pitisuttihum, Punnee; Kaewkungwal, Jaranit; Robb, Merlin L; Michael, Nelson L; Mullins, James I; Kim, Jerome H; Gilbert, Peter B; Rolland, Morgane

    2015-10-01

    Given the variation in the HIV-1 viral load (VL) set point across subjects, as opposed to a fairly stable VL over time within an infected individual, it is important to identify the characteristics of the host and virus that affect VL set point. Although recently infected individuals with multiple phylogenetically linked HIV-1 founder variants represent a minority of HIV-1 infections, we found--n two different cohorts--hat more diverse HIV-1 populations in early infection were associated with significantly higher VL 1 year after HIV-1 diagnosis. PMID:26322580

  17. HIV-1 infections with multiple founders are associated with higher viral loads than infections with single founders

    PubMed Central

    Janes, Holly; Herbeck, Joshua T.; Tovanabutra, Sodsai; Thomas, Rasmi; Frahm, Nicole; Duerr, Ann; Hural, John; Corey, Lawrence; Self, Steve G.; Buchbinder, Susan P.; McElrath, M. Juliana; O'Connell, Robert J.; Paris, Robert M.; Rerks-Ngarm, Supachai; Nitayaphan, Sorachai; Pitisuttihum, Punnee; Kaewkungwal, Jaranit; Robb, Merlin L.; Michael, Nelson L.; Mullins, James I.; Kim, Jerome H.; Gilbert, Peter B.; Rolland, Morgane

    2015-01-01

    Given the wide differences in HIV-1 viral load (VL) setpoint across subjects as opposed to fairly stable VL over time within an infected individual, it is important to identify host and viral characteristics that affect VL setpoint. While recently-infected individuals with multiple phylogenetically-linked HIV-1 founder variants represent a minority of HIV-1 infections, we found in two different cohorts that more diverse HIV-1 populations in early infection were associated with significantly higher VL one year after HIV-1 diagnosis. PMID:26322580

  18. An entropy-based measure of founder informativeness.

    PubMed

    Reyes-Valdés, M Humberto; Williams, Claire G

    2005-02-01

    Optimizing quantitative trait locus (QTL) mapping experiments requires a generalized measure of marker informativeness because variable information is obtained from different marker systems, marker distribution and pedigree types. Such a measure can be derived from the concept of Shannon entropy, a central concept in information theory. Here we introduce entropy-based founder informativeness (EFI), a new measure of information content generalized across pedigrees, maps, marker systems and mating configurations. We derived equations for inbred- and outbred-derived mapping populations. Mathematical properties of EFI include enhanced sensitivity to mapping population type and extension to any number of founders. To illustrate the use of EFI, we compared experimental designs for QTL mapping for three examples: (i) different marker systems for an F2 pedigree, (ii) different marker densities and sampling sizes for a BC1 pedigree and (iii) a comparison of haplotypic versus zygotic analyses of an outbred pedigree. As an a priori generalized measure of information content, EFI does not require phenotypic data for optimizing experimental designs for QTL mapping. PMID:16089038

  19. Founder mutation for Huntington disease in Caucasus Jews.

    PubMed

    Melamed, O; Behar, D M; Bram, C; Magal, N; Pras, E; Reznik-Wolf, H; Borochowitz, Z U; Davidov, B; Mor-Cohen, R; Baris, H N

    2015-02-01

    Huntington disease (HD), an autosomal dominant disorder involving HTT, is characterized by chorea, psychiatric illness and cognitive decline. Diagnosis and age of onset depend on the degree of expansion of the trinucleotide CAG repeat within the gene. The prevalence of HD is known for Europeans but has not been studied in the Israeli population. Between 2006 and 2011 we diagnosed in our adult genetics clinic ten HD probands, nine of whom were Caucasus Jews (CJ) (Azerbaijani), and one Ashkenazi Jewish. We performed haplotype analysis to look for evidence of a founder mutation, and found that of the nine CJ, eight shared the same haplotype that was compatible with the A1 haplogroup. We calculated the coalescence age of the mutation to be between 80 and 150 years. Ninety percent of our HD patients are CJ, as are 27% of the HD patients in Israel, although the CJ comprise only 1.4% of the Israeli population. Our findings suggest a higher prevalence of HD among CJ compared to the general Israeli population and are consistent with a recent founder mutation. We recommend a higher degree of suspicion for HD in CJ with subtle clinical findings. PMID:24405192

  20. Founder effects initiated rapid species radiation in Hawaiian cave planthoppers.

    PubMed

    Wessel, Andreas; Hoch, Hannelore; Asche, Manfred; von Rintelen, Thomas; Stelbrink, Björn; Heck, Volker; Stone, Fred D; Howarth, Francis G

    2013-06-01

    The Hawaiian Islands provide the venue of one of nature's grand experiments in evolution. Here, we present morphological, behavioral, genetic, and geologic data from a young subterranean insect lineage in lava tube caves on Hawai'i Island. The Oliarus polyphemus species complex has the potential to become a model for studying rapid speciation by stochastic events. All species in this lineage live in extremely similar environments but show strong differentiation in behavioral and morphometric characters, which are random with respect to cave age and geographic distribution. Our observation that phenotypic variability within populations decreases with increasing cave age challenges traditional views on founder effects. Furthermore, these cave populations are natural replicates that can be used to test the contradictory hypotheses. Moreover, Hawaiian cave planthoppers exhibit one of the highest speciation rates among animals and, thus, radically shift our perception on the evolutionary potential of obligate cavernicoles. PMID:23696661

  1. Founder effects initiated rapid species radiation in Hawaiian cave planthoppers

    PubMed Central

    Wessel, Andreas; Hoch, Hannelore; Asche, Manfred; von Rintelen, Thomas; Stelbrink, Björn; Heck, Volker; Stone, Fred D.; Howarth, Francis G.

    2013-01-01

    The Hawaiian Islands provide the venue of one of nature’s grand experiments in evolution. Here, we present morphological, behavioral, genetic, and geologic data from a young subterranean insect lineage in lava tube caves on Hawai‘i Island. The Oliarus polyphemus species complex has the potential to become a model for studying rapid speciation by stochastic events. All species in this lineage live in extremely similar environments but show strong differentiation in behavioral and morphometric characters, which are random with respect to cave age and geographic distribution. Our observation that phenotypic variability within populations decreases with increasing cave age challenges traditional views on founder effects. Furthermore, these cave populations are natural replicates that can be used to test the contradictory hypotheses. Moreover, Hawaiian cave planthoppers exhibit one of the highest speciation rates among animals and, thus, radically shift our perception on the evolutionary potential of obligate cavernicoles. PMID:23696661

  2. Founders' Sensemaking and Sensegiving Behaviors Effect on the Organizational Identities of New Charter Schools

    ERIC Educational Resources Information Center

    Fehsenfeld, Corie

    2010-01-01

    This qualitative, multiple case study looked at the emerging organizational identity of four charter schools during the early years of development and the influence of the founder on that developing identity. The study looked at the ways in which each founder's sensemaking and sensegiving behaviors may have influenced the organizational identity…

  3. Origins, admixture and founder lineages in European Roma.

    PubMed

    Martínez-Cruz, Begoña; Mendizabal, Isabel; Harmant, Christine; de Pablo, Rosario; Ioana, Mihai; Angelicheva, Dora; Kouvatsi, Anastasia; Makukh, Halyna; Netea, Mihai G; Pamjav, Horolma; Zalán, Andrea; Tournev, Ivailo; Marushiakova, Elena; Popov, Vesselin; Bertranpetit, Jaume; Kalaydjieva, Luba; Quintana-Murci, Lluis; Comas, David

    2016-06-01

    The Roma, also known as 'Gypsies', represent the largest and the most widespread ethnic minority of Europe. There is increasing evidence, based on linguistic, anthropological and genetic data, to suggest that they originated from the Indian subcontinent, with subsequent bottlenecks and undetermined gene flow from/to hosting populations during their diaspora. Further support comes from the presence of Indian uniparentally inherited lineages, such as mitochondrial DNA M and Y-chromosome H haplogroups, in a significant number of Roma individuals. However, the limited resolution of most genetic studies so far, together with the restriction of the samples used, have prevented the detection of other non-Indian founder lineages that might have been present in the proto-Roma population. We performed a high-resolution study of the uniparental genomes of 753 Roma and 984 non-Roma hosting European individuals. Roma groups show lower genetic diversity and high heterogeneity compared with non-Roma samples as a result of lower effective population size and extensive drift, consistent with a series of bottlenecks during their diaspora. We found a set of founder lineages, present in the Roma and virtually absent in the non-Roma, for the maternal (H7, J1b3, J1c1, M18, M35b, M5a1, U3, and X2d) and paternal (I-P259, J-M92, and J-M67) genomes. This lineage classification allows us to identify extensive gene flow from non-Roma to Roma groups, whereas the opposite pattern, although not negligible, is substantially lower (up to 6.3%). Finally, the exact haplotype matching analysis of both uniparental lineages consistently points to a Northwestern origin of the proto-Roma population within the Indian subcontinent. PMID:26374132

  4. An Ashkenazi founder mutation in the PKHD1 gene.

    PubMed

    Quint, Adina; Sagi, Michal; Carmi, Shai; Daum, Hagit; Macarov, Michal; Ben Neriah, Ziva; Meiner, Vardiela; Elpeleg, Orly; Lerer, Israela

    2016-02-01

    Autosomal recessive polycystic kidney disease (ARPKD) is usually detected late in pregnancies in embryos with large echogenic kidneys accompanied by oligohydramnios. Hundreds of private pathogenic variants have been identified in the large PKHD1 gene in various populations. Yet, because of the large size of the gene, segregation analysis of microsatellite polymorphic markers residing in the PKDH1 locus has commonly been utilized for prenatal diagnosis. Keeping in mind the limitations of this strategy, we utilized it for testing 7 families with affected fetuses or newborns, of which in 5 at least one parent was Ashkenazi, and identified that the same haplotype was shared by the majority of the Ashkenazi parents (7/9). This led us to suspect that they carry the same founder mutation. Whole Exome analysis of DNA from a fetus of one of the families detected an already known pathogenic variant c.3761_3762delCCinsG, an indel variant resulting in frameshift (p.Ala1254GlyfsX49). This variant was detected in 9 parents (5 families), of them 7 individuals were Ashkenazi and one Moroccan Jew who shared the same haplotype, and one Ashkenazi, who carried the same variant on a recombinant haplotype. Screening for this variant in 364 Ashkenazi individuals detected 2 carriers. These findings suggest that although c.3761_3762delCCinsG is considered one of the frequent variants detected in unrelated individuals, and was thought to have occurred independently on various haplotypes, it is in fact a founder mutation in the Ashkenazi population. PMID:26721323

  5. A haplotypic approach to founder-origin probabilities and outbred QTL analysis.

    PubMed

    Reyes-Valdès, M Humberto; Williams, Claire G

    2002-12-01

    Founder-origin probability methods are used to trace specific chromosomal segments in individual offspring. A haplotypic method was developed for calculating founder-origin probabilities in three-generation outbred pedigrees suited to quantitative trait locus (QTL) analysis. Estimators for expected founder-origin proportions were derived for a linkage group segment, an entire linkage group and a complete haplotype. If the founders are truly outbred, the haplotypic method gives a close approximation when compared with the Haley et al. (1994) method that simultaneously uses all marker information for QTL analysis, and it is less computationally demanding. The chief limitation of the haplotypic method is that some information in two-allele intercross marker-type configurations is ignored. Informativeness of marker arrays is discussed in the framework of founder-origin probabilities and proportions. The haplotypic method can be extended to more complex pedigrees with additional generations. PMID:12688662

  6. Identification of kin structure among Guam rail founders: a comparison of pedigrees and DNA profiles

    USGS Publications Warehouse

    Haig, Susan M.; Ballou, J.D.; Casna, N.J.

    1994-01-01

    Kin structure among founders can have a significant effect on subsequent population structure. Here we use the correlation between DNA profile similarity and relatedness calculated from pedigrees to test hypotheses regarding kin structure among founders to the captive Guam rail (Rallus owstoni) population. Five different pedigrees were generated under the following hypotheses: (i) founders are unrelated; (ii) founders are unrelated except for same-nest chicks; (iii) founders from the same major site are siblings; (iv) founders from the same local site are siblings; and (v) founders are related as defined by a UPGMA cluster analysis of DNA similarity data. Relatedness values from pedigrees 1, 2 and 5 had the highest correlation with DNA similarity but the correlation between relatedness and similarity were not significantly different among pedigrees. Pedigree 5 resulted in the highest correlation overall when using only relatedness values that changed as a result of different founder hypotheses. Thus, founders were assigned relatedness based on pedigree 5 because it had the highest correlations with DNA similarity, was the most conservative approach, and incorporated all field data. The analyses indicated that estimating relatedness using DNA profiles remains problematic, therefore we compared mean kinship, a measure of genetic importance, with mean DNA profile similarity to determine if genetic importance among individuals could be determined via use of DNA profiles alone. The significant correlation suggests this method may provide more information about population structure than was previously thought. Thus, DNA profiles can provide a reasonable explanation for founder relatedness and mean DNA profile similarity may be helpful in determining relative genetic importance of individuals when detailed pedigrees are absent.

  7. Limb-girdle muscular dystrophy in the Agarwals: Utility of founder mutations in CAPN3 gene

    PubMed Central

    Khadilkar, Satish V.; Chaudhari, Chetan R.; Dastur, Rashna S.; Gaitonde, Pradnya S.; Yadav, Jayendra G.

    2016-01-01

    Background and Purpose: Diagnostic evaluation of limb-girdle muscular dystrophy type 2A (LGMD2A) involves specialized studies on muscle biopsy and mutation analysis. Mutation screening is the gold standard for diagnosis but is difficult as the gene is large and multiple mutations are known. This study evaluates the utility of two known founder mutations as a first-line diagnostic test for LGMD2A in the Agarwals. Materials and Methods: The Agarwals with limb-girdle muscular dystrophy (LGMD) phenotype were analyzed for two founder alleles (intron 18/exon 19 c.2051-1G>T and exon 22 c.2338G>C). Asymptomatic first-degree relatives of patients with genetically confirmed mutations and desirous of counseling were screened for founder mutations. Results: Founder alleles were detected in 26 out of 29 subjects with LGMD phenotype (89%). The most common genotype observed was homozygous for exon 22 c.2338 G>C mutation followed by compound heterozygosity. Single founder allele was identified in two. Single allele was detected in two of the five asymptomatic relatives. Conclusion: Eighty-nine percent of the Agarwals having LGMD phenotype have LGMD2A resulting from founder mutations. Founder allele analysis can be utilized as the initial noninvasive diagnostic step for index cases, carrier detection, and counseling. PMID:27011640

  8. Mediterranean Founder Mutation Database (MFMD): Taking Advantage from Founder Mutations in Genetics Diagnosis, Genetic Diversity and Migration History of the Mediterranean Population.

    PubMed

    Charoute, Hicham; Bakhchane, Amina; Benrahma, Houda; Romdhane, Lilia; Gabi, Khalid; Rouba, Hassan; Fakiri, Malika; Abdelhak, Sonia; Lenaers, Guy; Barakat, Abdelhamid

    2015-11-01

    The Mediterranean basin has been the theater of migration crossroads followed by settlement of several societies and cultures in prehistoric and historical times, with important consequences on genetic and genomic determinisms. Here, we present the Mediterranean Founder Mutation Database (MFMD), established to offer web-based access to founder mutation information in the Mediterranean population. Mutation data were collected from the literature and other online resources and systematically reviewed and assembled into this database. The information provided for each founder mutation includes DNA change, amino-acid change, mutation type and mutation effect, as well as mutation frequency and coalescence time when available. Currently, the database contains 383 founder mutations found in 210 genes related to 219 diseases. We believe that MFMD will help scientists and physicians to design more rapid and less expensive genetic diagnostic tests. Moreover, the coalescence time of founder mutations gives an overview about the migration history of the Mediterranean population. MFMD can be publicly accessed from http://mfmd.pasteur.ma. PMID:26173767

  9. Genetic Comparison of a Croatian Isolate and CEPH European Founders

    PubMed Central

    Navarro, Pau; Vitart, Véronique; Hayward, Caroline; Tenesa, Albert; Zgaga, Lina; Juricic, Danica; Polasek, Ozren; Hastie, Nicholas D; Rudan, Igor; Campbell, Harry; Wright, Alan F; Haley, Chris S; Knott, Sara A

    2010-01-01

    Human isolates have been postulated as a good resource for the identification of QTL due to reduced genetic diversity and a more homogeneous environment. Isolates may also have increased linkage disequilibrium (LD) due to small effective population size and, either loss or increase in frequency of alleles that are rare in the general population from which they originate. Here we investigate the difference in allele and genotype frequencies, LD and homozygous tracts between an isolate—several villages from the island of Vis in Croatia—and an outbred population of European origin: the Hapmap CEPH founders. Using the HumanHap300 v1 Genotyping BeadChip, we show that our population does not differ greatly from the reference CEU outbred population despite having a slightly higher proportion of monomorphic loci, a slightly higher long-range LD, and a greater proportion of individuals with long homozygous tracts. We conclude that genotyping arrays should perform equally well in our isolate as in outbred European populations for disease mapping studies and that SNP–trait associations discovered in our well-characterized Croatian isolate should be valid in the general European population from which they descend. Genet. Epidemiol. 34: 140–145, 2010. © 2009 Wiley-Liss, Inc. PMID:19697321

  10. Long-distance plant dispersal to North Atlantic islands: colonization routes and founder effect

    PubMed Central

    Alsos, Inger Greve; Ehrich, Dorothee; Eidesen, Pernille Bronken; Solstad, Heidi; Westergaard, Kristine Bakke; Schönswetter, Peter; Tribsch, Andreas; Birkeland, Siri; Elven, Reidar; Brochmann, Christian

    2015-01-01

    Long-distance dispersal (LDD) processes influence the founder effect on islands. We use genetic data for 25 Atlantic species and similarities among regional floras to analyse colonization, and test whether the genetic founder effect on five islands is associated with dispersal distance, island size and species traits. Most species colonized postglacially via multiple dispersal events from several source regions situated 280 to >3000 km away, and often not from the closest ones. A strong founder effect was observed for insect-pollinated mixed maters, and it increased with dispersal distance and decreased with island size in accordance with the theory of island biogeography. Only a minor founder effect was observed for wind-pollinated outcrossing species. Colonization patterns were largely congruent, indicating that despite the importance of stochasticity, LDD is mainly determined by common factors, probably dispersal vectors. Our findings caution against a priori assuming a single, close source region in biogeographic analyses. PMID:25876627

  11. Founder mutations in Tunisia: implications for diagnosis in North Africa and Middle East

    PubMed Central

    2012-01-01

    Background Tunisia is a North African country of 10 million inhabitants. The native background population is Berber. However, throughout its history, Tunisia has been the site of invasions and migratory waves of allogenic populations and ethnic groups such as Phoenicians, Romans, Vandals, Arabs, Ottomans and French. Like neighbouring and Middle Eastern countries, the Tunisian population shows a relatively high rate of consanguinity and endogamy that favor expression of recessive genetic disorders at relatively high rates. Many factors could contribute to the recurrence of monogenic morbid trait expression. Among them, founder mutations that arise in one ancestral individual and diffuse through generations in isolated communities. Method We report here on founder mutations in the Tunisian population by a systematic review of all available data from PubMed, other sources of the scientific literature as well as unpublished data from our research laboratory. Results We identified two different classes of founder mutations. The first includes founder mutations so far reported only among Tunisians that are responsible for 30 genetic diseases. The second group represents founder haplotypes described in 51 inherited conditions that occur among Tunisians and are also shared with other North African and Middle Eastern countries. Several heavily disabilitating diseases are caused by recessive founder mutations. They include, among others, neuromuscular diseases such as congenital muscular dystrophy and spastic paraglegia and also severe genodermatoses such as dystrophic epidermolysis bullosa and xeroderma pigmentosa. Conclusion This report provides informations on founder mutations for 73 genetic diseases either specific to Tunisians or shared by other populations. Taking into account the relatively high number and frequency of genetic diseases in the region and the limited resources, screening for these founder mutations should provide a rapid and cost effective tool for

  12. Genetic Studies of Stuttering in a Founder Population

    PubMed Central

    Wittke-Thompson, Jacqueline K.; Ambrose, Nicoline; Yairi, Ehud; Roe, Cheryl; Cook, Edwin H.; Ober, Carole; Cox, Nancy J.

    2007-01-01

    Genome-wide linkage and association analyses were conducted to identify genetic determinants of stuttering in a founder population in which 48 individuals affected with stuttering are connected in a single 232-person genealogy. A novel approach was devised to account for all necessary relationships to enable multipoint linkage analysis. Regions with nominal evidence for linkage were found on chromosomes 3 (P=0.013, 208.8 centiMorgans (cM)), 13 (P=0.012, 52.6 cM), and 15 (P=0.02, 100 cM). Regions with nominal evidence for association with stuttering that overlapped with a linkage signal are located on chromosomes 3 (P=0.0047, 195 cM), 9 (P=0.0067, 46.5 cM), and 13 (P=0.0055, 52.6 cM). We also conducted the first meta-analysis for stuttering using results from linkage studies in the Hutterites and The Illinois International Genetics of Stuttering Project and identified regions with nominal evidence for linkage on chromosomes 2 (P=0.013, 180–195 cM) and 5 (P=0.0051, 105–120 cM; P=0.015, 120–135 cM). None of the linkage signals detected in the Hutterite sample alone, or in the meta-analysis, meet genome-wide criteria for significance, although some of the stronger signals overlap linkage mapping signals previously reported for other speech and language disorders. PMID:17276504

  13. Dystonia in Ashkenazi Jews: clinical characterization of a founder mutation.

    PubMed

    Bressman, S B; de Leon, D; Kramer, P L; Ozelius, L J; Brin, M F; Greene, P E; Fahn, S; Breakefield, X O; Risch, N J

    1994-11-01

    A gene (DYT1) for idiopathic torsion dystonia maps to chromosome 9q34 in Ashkenazi Jewish families with early onset of symptoms. Further, there is linkage disequilibrium between DYT1 and a particular haplotype of alleles at 9q34 loci in this population. This implies that a large proportion of early-onset idiopathic torsion dystonia in Ashkenazi Jews is due to a founder mutation in DYT1. To characterize the phenotypic range of this mutation, we studied 174 Ashkenazi Jewish individuals affected with idiopathic torsion dystonia. We used GT(n) markers on chromosome 9q34 (D9S62, D9S63, and ASS) and classified individuals as having ("carriers"), not having ("noncarriers"), or being ambiguous with respect to a DYT1-associated haplotype. We assessed clinical features and found marked clinical differences between haplotype carriers and noncarriers. There were 90 carriers, 70 noncarriers, and 14 ambiguous individuals. The mean age at onset of symptoms was significantly lower in carriers than in noncarriers (12.5 +/- 8.2 vs 36.5 +/- 16.4 years). In 94% of carriers, symptoms began in a limb (arm or leg equally); rarely the disorder started in the neck (3.3%) or larynx (2.2%). In contrast, the neck, larynx, and other cranial muscles were the sites of onset in 79% of noncarriers; onset in the arms occurred in 21% and onset in the legs never occurred. Limb onset, leg involvement in the course of disease, and age at onset distinguished haplotype carriers from noncarriers with 90% accuracy. In conclusion, there are clinical differences between Ashkenazi Jewish individuals with idiopathic torsion dystonia who do or do not have a unique DYT1 mutation, as determined by a DYT1-associated haplotype of 9q34 alleles.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7979224

  14. Legacy of mutiny on the Bounty: founder effect and admixture on Norfolk Island

    PubMed Central

    Macgregor, Stuart; Bellis, Claire; Lea, Rod A; Cox, Hannah; Dyer, Tom; Blangero, John; Visscher, Peter M; Griffiths, Lyn R

    2010-01-01

    The population of Norfolk Island, located off the eastern coast of Australia, possesses an unusual and fascinating history. Most present-day islanders are related to a small number of the ‘Bounty' mutineer founders. These founders consisted of Caucasian males and Polynesian females and led to an admixed present-day population. By examining a single large pedigree of 5742 individuals, spanning >200 years, we analyzed the influence of admixture and founder effect on various cardiovascular disease (CVD)-related traits. On account of the relative isolation of the population, on average one-third of the genomes of present-day islanders (single large pedigree individuals) is derived from 17 initial founders. The proportion of Polynesian ancestry in the present-day individuals was found to significantly influence total triglycerides, body mass index, systolic blood pressure and diastolic blood pressure. For various cholesterol traits, the influence of ancestry was less marked but overall the direction of effect for all CVD-related traits was consistent with Polynesian ancestry conferring greater CVD risk. Marker-derived homozygosity was computed and agreed with measures of inbreeding derived from pedigree information. Founder effect (inbreeding and marker-derived homozygosity) significantly influenced height. In conclusion, both founder effect and extreme admixture have substantially influenced the genetic architecture of a variety of CVD-related traits in this population. PMID:19584896

  15. New insights on lithospheric foundering from thermo-mechanically coupled numerical modelling

    NASA Astrophysics Data System (ADS)

    Pastor-Galán, Daniel; Thieulot, Cedric

    2015-04-01

    Earth's lithosphere is recycled into the mantle as required by global mass considerations. At least during the latest 1 G.y. the main mechanism of lithospheric foundering into the mantle has been subduction. Yet other mechanisms of mantle removal such as Rayleigh-Taylor-type instability or delamination have significant influence at present as revealed by mantle anomalies, and are considered to be likely candidates for the main recycling mechanisms of lithospheric during the Archean. Although lithospheric mantle removal has been geophysically imaged, e.g. Carpathians, Colorado Plateau, at many other locations geophysical and geological observations also seem to indicate that mantle lithosphere is anomalously thin or absent. Potential places where lithospheric mantle foundering processes took place are The Urals, the Variscides, underneath the Ibero Armorican Orocline in western Europe, and the Tibetan, Puna and Anatolian Plateaus. Lithospheric foundering has been blamed for, among others, cratonization processes, rapid surface uplift, generation of voluminous magmatism, changes in crustal stress from compression to extension and a long etc. However, its triggering mechanisms are not well studied, and a variety of possible explanations have been given for lithospheric foundering processes, including convective instability following orogenic thickening or some other perturbation of thermal boundary layers, development of eclogitic roots, erosion of the lithosphere by a flat-subducting slab or partial melting of the asthenosphere, and partial intruding pyroxenites into the base of lithosphere. To understand the mechanisms, causes and consequences of lithospheric foundering, we explored lithospheric foundering in an assortment of scenarios using the numerical code, ELEFANT, an user-friendly multipurpose geodynamics code. Preliminary results indicate that changes in geometry, thermal state and composition of the lithosphere, associated with mantle flow, can have a first

  16. Prevalence and impact of founder mutations in hereditary breast cancer in Latin America

    PubMed Central

    Ashton-Prolla, Patricia; Vargas, Fernando Regla

    2014-01-01

    Approximately 10% of all cancers are considered hereditary and are primarily caused by germline, high penetrance mutations in cancer predisposition genes. Although most cancer predisposition genes are considered molecularly heterogeneous, displaying hundreds of different disease-causing sequence alterations, founder mutations have been identified in certain populations. In some Latin American countries, founder mutations associated with increased risk of breast and other cancers have been described. This is particularly interesting considering that in most of these countries, populations are highly admixed with genetic contributions from native populations and from the in-flux of several distinct populations of immigrants. In this article, we present a review of the scientific literature on the subject and describe current data available on founder mutations described in the most common breast cancer predisposition genes: BRCA1, BRCA2 and TP53. PMID:24764757

  17. Genetics of murine craniofacial morphology: diallel analysis of the eight founders of the Collaborative Cross.

    PubMed

    Percival, Christopher J; Liberton, Denise K; Pardo-Manuel de Villena, Fernando; Spritz, Richard; Marcucio, Ralph; Hallgrímsson, Benedikt

    2016-01-01

    Using eight inbred founder strains of the mouse Collaborative Cross (CC) project and their reciprocal F1 hybrids, we quantified variation in craniofacial morphology across mouse strains, explored genetic contributions to craniofacial variation that distinguish the founder strains, and tested whether specific or summary measures of craniofacial shape display stronger additive genetic contributions. This study thus provides critical information about phenotypic diversity among CC founder strains and about the genetic contributions to this phenotypic diversity, which is relevant to understanding the basis of variation in standard laboratory strains and natural populations. Craniofacial shape was quantified as a series of size-adjusted linear dimensions (RDs) and by principal components (PC) analysis of morphological landmarks captured from computed tomography images from 62 of the 64 reciprocal crosses of the CC founder strains. We first identified aspects of skull morphology that vary between these phenotypically 'normal' founder strains and that are defining characteristics of these strains. We estimated the contributions of additive and various non-additive genetic factors to phenotypic variation using diallel analyses of a subset of these strongly differing RDs and the first eight PCs of skull shape variation. We find little difference in the genetic contributions to RD measures and PC scores, suggesting fundamental similarities in the magnitude of genetic contributions to both specific and summary measures of craniofacial phenotypes. Our results indicate that there are stronger additive genetic effects associated with defining phenotypic characteristics of specific founder strains, suggesting these distinguishing measures are good candidates for use in genotype-phenotype association studies of CC mice. Our results add significantly to understanding of genotype-phenotype associations in the skull, which serve as a foundation for modeling the origins of medically

  18. Founder mutation causing infantile GM1-gangliosidosis in the Gypsy population.

    PubMed

    Sinigerska, Ivanka; Chandler, David; Vaghjiani, Vijesh; Hassanova, Irfet; Gooding, Rebecca; Morrone, Amelia; Kremensky, Ivo; Kalaydjieva, Luba

    2006-05-01

    The Gypsies are a trans-national founder population of Asian descent, whose genetic heritage is still incompletely characterized. Here, we describe the first founder mutation leading to a lysosomal storage disorder in this population: R59H in GLB1, which causes infantile GM1-gangliosidosis. The R59H carrier rate is approximately 2% in the general Gypsy population and approximately 10% in the Rudari sub-isolate. Haplotype analysis suggests that the Gypsy diaspora may have contributed to the spread of this mutation to South America. PMID:16466959

  19. A Population-Genetic Test of Founder Effects and Implications for Ashkenazi Jewish Diseases

    PubMed Central

    Slatkin, Montgomery

    2004-01-01

    A founder effect can account for the presence of an allele at an unusually high frequency in an isolated population if the allele is selectively neutral and if all copies are identical by descent with a copy that either was carried by a founder individual or arose by mutation later. Here, a statistical test of both aspects of the founder-effect hypothesis is developed. The test is performed by a modified version of a program that implements the Slatkin-Bertorelle test of neutrality. The test is applied to several disease-associated alleles found predominantly in Ashkenazi Jews. Despite considerable uncertainty about the demographic history of Ashkenazi Jews and their ancestors, available genetic data are consistent with a founder effect resulting from a severe bottleneck in population size between a.d. 1100 and a.d. 1400 and an earlier bottleneck in a.d. 75, at the beginning of the Jewish Diaspora. The relatively high frequency of alleles causing four different lysosomal storage disorders, including Tay-Sachs disease and Gaucher disease, can be accounted for if the disease-associated alleles are recessive in their effects on reproductive fitness. PMID:15208782

  20. Hallie Quinn Brown (1845-Or 1850-1949): Educator, Author, Lecturer, Founder, and Reformer

    ERIC Educational Resources Information Center

    Evans, A.L.; Lamikanra, A.E.; Jones, O.S.L.; Evans, V.

    2004-01-01

    Most black educators are aware of black pioneers, such as Frederick Douglass, Phillis Wheatley, Booker T. Washington, W. E. B. DuBois, George Washington Carver, Mary McLeod Bethune, and others, Few are, however, aware of Hallie Quinn Brown (1845-or 1850-1949) educator, author, lecture, founder, and reformer, who wrote one of the first biographies…

  1. Optimization methods for selecting founder individuals for captive breeding or reintroduction of endangered species.

    PubMed

    Miller, Webb; Wright, Stephen J; Zhang, Yu; Schuster, Stephan C; Hayes, Vanessa M

    2010-01-01

    Methods from genetics and genomics can be employed to help save endangered species. One potential use is to provide a rational strategy for selecting a population of founders for a captive breeding program. The hope is to capture most of the available genetic diversity that remains in the wild population, to provide a safe haven where representatives of the species can be bred, and eventually to release the progeny back into the wild. However, the founders are often selected based on a random-sampling strategy whose validity is based on unrealistic assumptions. Here we outline an approach that starts by using cutting-edge genome sequencing and genotyping technologies to objectively assess the available genetic diversity. We show how combinatorial optimization methods can be applied to these data to guide the selection of the founder population. In particular, we develop a mixed-integer linear programming technique that identifies a set of animals whose genetic profile is as close as possible to specified abundances of alleles (i.e., genetic variants), subject to constraints on the number of founders and their genders and ages. PMID:19908356

  2. A population-genetic test of founder effects and implications for Ashkenazi Jewish diseases.

    PubMed

    Slatkin, Montgomery

    2004-08-01

    A founder effect can account for the presence of an allele at an unusually high frequency in an isolated population if the allele is selectively neutral and if all copies are identical by descent with a copy that either was carried by a founder individual or arose by mutation later. Here, a statistical test of both aspects of the founder-effect hypothesis is developed. The test is performed by a modified version of a program that implements the Slatkin-Bertorelle test of neutrality. The test is applied to several disease-associated alleles found predominantly in Ashkenazi Jews. Despite considerable uncertainty about the demographic history of Ashkenazi Jews and their ancestors, available genetic data are consistent with a founder effect resulting from a severe bottleneck in population size between a.d. 1100 and a.d. 1400 and an earlier bottleneck in a.d. 75, at the beginning of the Jewish Diaspora. The relatively high frequency of alleles causing four different lysosomal storage disorders, including Tay-Sachs disease and Gaucher disease, can be accounted for if the disease-associated alleles are recessive in their effects on reproductive fitness. PMID:15208782

  3. Estimation of Epistatic Variance Components and Heritability in Founder Populations and Crosses

    PubMed Central

    Young, Alexander I.; Durbin, Richard

    2014-01-01

    Genetic association studies have explained only a small proportion of the estimated heritability of complex traits, leaving the remaining heritability “missing.” Genetic interactions have been proposed as an explanation for this, because they lead to overestimates of the heritability and are hard to detect. Whether this explanation is true depends on the proportion of variance attributable to genetic interactions, which is difficult to measure in outbred populations. Founder populations exhibit a greater range of kinship than outbred populations, which helps in fitting the epistatic variance. We extend classic theory to founder populations, giving the covariance between individuals due to epistasis of any order. We recover the classic theory as a limit, and we derive a recently proposed estimator of the narrow sense heritability as a corollary. We extend the variance decomposition to include dominance. We show in simulations that it would be possible to estimate the variance from pairwise interactions with samples of a few thousand from strongly bottlenecked human founder populations, and we provide an analytical approximation of the standard error. Applying these methods to 46 traits measured in a yeast (Saccharomyces cerevisiae) cross, we estimate that pairwise interactions explain 10% of the phenotypic variance on average and that third- and higher-order interactions explain 14% of the phenotypic variance on average. We search for third-order interactions, discovering an interaction that is shared between two traits. Our methods will be relevant to future studies of epistatic variance in founder populations and crosses. PMID:25326236

  4. Genome-wide patterns of identity-by-descent sharing in the French Canadian founder population

    PubMed Central

    Gauvin, Héloïse; Moreau, Claudia; Lefebvre, Jean-François; Laprise, Catherine; Vézina, Hélène; Labuda, Damian; Roy-Gagnon, Marie-Hélène

    2014-01-01

    In genetics the ability to accurately describe the familial relationships among a group of individuals can be very useful. Recent statistical tools succeeded in assessing the degree of relatedness up to 6–7 generations with good power using dense genome-wide single-nucleotide polymorphism data to estimate the extent of identity-by-descent (IBD) sharing. It is therefore important to describe genome-wide patterns of IBD sharing for more remote and complex relatedness between individuals, such as that observed in a founder population like Quebec, Canada. Taking advantage of the extended genealogical records of the French Canadian founder population, we first compared different tools to identify regions of IBD in order to best describe genome-wide IBD sharing and its correlation with genealogical characteristics. Results showed that the extent of IBD sharing identified with FastIBD correlates best with relatedness measured using genealogical data. Total length of IBD sharing explained 85% of the genealogical kinship's variance. In addition, we observed significantly higher sharing in pairs of individuals with at least one inbred ancestor compared with those without any. Furthermore, patterns of IBD sharing and average sharing were different across regional populations, consistent with the settlement history of Quebec. Our results suggest that, as expected, the complex relatedness present in founder populations is reflected in patterns of IBD sharing. Using these patterns, it is thus possible to gain insight on the types of distant relationships in a sample from a founder population like Quebec. PMID:24129432

  5. The Influence of Founder Type on Charter School Structures and Operations.

    ERIC Educational Resources Information Center

    Henig, Jeffrey R.; Holyoke, Thomas T.; Brown, Heath; Lacireno-Paquet, Natalie

    Much of the literature on charter schools treats them as an undifferentiated mass. A typology of charter schools grounded in the norms, traditions, and perspectives of the founding organization or organizers is presented and tested in this paper. It is suggested that there are two broad categories of charter founders: (1) those who are more…

  6. The Influence of Founder Type on Charter School Structures and Operations

    ERIC Educational Resources Information Center

    Henig, Jeffrey R.; Holyoke, Thomas T.; Brown, Heath; Lacireno-Paquet, Natalie

    2005-01-01

    Much of the literature on charter schools treats them as an undifferentiated mass. Here we present and test a typology of charter schools that is grounded in the norms, traditions, and perspectives of the founding organization or organizers. We suggest that there are two broad categories of charter founders--those who are more mission oriented and…

  7. A. G. Vernon Harcourt: A Founder of Chemical Kinetics and a Friend of "Lewis Carroll."

    ERIC Educational Resources Information Center

    Shorter, John

    1980-01-01

    Outlines the life of A. G. Vernon Harcourt, a founder of chemical kinetics, contributor to the purification of coal gas from sulfur compounds, inventor of the percentage chloroform inhaler, friend to Lewis Carroll, and instructor to the Prince of Wales. (CS)

  8. 171. Credit PG&E. Hamden Holmes Noble, founder of the Keswick ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    171. Credit PG&E. Hamden Holmes Noble, founder of the Keswick Electric Power Company. President of Keswick Power and its successor companies -- Northern California Power Company and Northern California Power Company, Consolidated (until 1915). - Battle Creek Hydroelectric System, Battle Creek & Tributaries, Red Bluff, Tehama County, CA

  9. Molecular Diagnosis of Hereditary Fructose Intolerance: Founder Mutation in a Community from India.

    PubMed

    Bijarnia-Mahay, Sunita; Movva, Sireesha; Gupta, Neerja; Sharma, Deepak; Puri, Ratna D; Kotecha, Udhaya; Saxena, Renu; Kabra, Madhulika; Mohan, Neelam; Verma, Ishwar C

    2015-01-01

    Hereditary fructose intolerance (HFI) is a difficult-to-confirm diagnosis, requiring either invasive liver biopsy-enzyme assay or potentially hazardous fructose challenge test or expensive molecular genetic analysis. Therefore, worldwide there has been a trend towards finding "common mutations" in distinct ethnic groups to simplify the process of diagnosis. The nonspecific presentation of the disease often leads to diagnostic confusion with other metabolic liver disorders such as glycogenoses, galactosemia, and tyrosinemia. This leads to much delay in diagnosis with consequent harm to the patient.We report mutations in the ALDOB gene, from eleven Indian patients, seven of whom belong to the Agarwal community. Six patients from the Agarwal community and two non-Agarwal patients harbored one novel mutation, c.324+1G>A (five homozygous and one heterozygous), in the ALDOB gene. Haplotyping performed in families confirmed a founder effect. The community has been known to harbor founder mutations in other genes such as the MLC1, PANK2, and CAPN3 genes, thus providing another evidence for a founder effect in the community in case of HFI. This may pave the path for a simpler and quicker test at least for this community in India. In addition to the founder mutation, we report four other novel mutations, c.112+1delG, c.380-1G>A, c.677G>A, and c.689delA, and a previously reported mutation, c.1013C>T, in the cohort from India. PMID:25595217

  10. The legacy of nuclear risk and the founder effect in biotechnology organizations.

    PubMed

    Fleising, Usher

    2002-04-01

    In the wake of the Chernobyl nuclear accident and a decline in the public trust of science, the founders of modern biotechnology recognized the strategic importance of risk assessment and regulatory affairs. In an effort to avoid the demonization that was attached to the nuclear industry, the pioneers of modern biotechnology delegated authority for regulatory negotiation and risk management to senior positions in the firm. At the same time, the Biotechnology Industry Organization was handed great latitude and trust with making public pronouncements on issues of bioethics and public policy. The way in which founders and leaders embed norms for negotiating regulation and responding to public perceptions has proved important in the maturation and acceptance of a biotechnology sector. PMID:11906747

  11. Molecular Investigation of Distal Renal Tubular Acidosis in Tunisia, Evidence for Founder Mutations

    PubMed Central

    Voskarides, Konstantinos; Nouira, Sonia; Ben Halim, Nizar; Kefi, Rym; Aloulou, Hajer; Romdhane, Lilia; Ben Abdallah, Rim; Ben Rhouma, Faten; Aissa, Khaoula; Boughamoura, Lamia; Kammoun, Thouraya; Azzouz, Hatem; Abroug, Saoussen; Ben Turkia, Hathemi; Ayadi, Abdelkarim; Mrad, Ridha; Chabchoub, Imen; Hachicha, Mongia; Chemli, Jalel; Deltas, Constantinos; Abdelhak, Sonia

    2014-01-01

    Background: Distal renal tubular acidosis (dRTA) is a rare genetic disease caused by mutations in different genes involved in the secretion of H+ ions in the intercalated cells of the collecting duct. Both autosomal dominant and recessive forms have been described; the latter is also associated with sensorineural hearing loss. Methods: Twenty-two Tunisian families were analyzed for mutations in the ATP6V1B1 and ATP6V0A4 genes by direct sequencing. Dating of the founder mutations was performed. Results: Two founder mutations in the ATP6V1B1 gene were found in 16/27 dRTA cases. The p.Ile386Hisfs*56 founder mutation was estimated to be older than 2400 years and no correlations were found with deafness. For the remaining patients, two mutations in the ATP6V0A4 gene, one of them being novel, were found in three Tunisian cases. The presence of a heterozygous missense mutation p.T30I, of the ATP6V1B1 gene, was identified in six patients, while no mutations of the second gene were detected. No deleterious mutations of either ATP6V1B1 or ATP6V0A were found for the two probands. Conclusion: Our study gives evidence of phenotypic and genotypic heterogeneity of dRTA in the Tunisian population. Five different mutations were found, two of them were due to a founder effect, and screening of these mutations could provide a rapid and valuable tool for diagnosis of dRTA. PMID:25285676

  12. Proof-of-principle rapid noninvasive prenatal diagnosis of autosomal recessive founder mutations

    PubMed Central

    Zeevi, David A.; Altarescu, Gheona; Weinberg-Shukron, Ariella; Zahdeh, Fouad; Dinur, Tama; Chicco, Gaya; Herskovitz, Yair; Renbaum, Paul; Elstein, Deborah; Levy-Lahad, Ephrat; Rolfs, Arndt; Zimran, Ari

    2015-01-01

    BACKGROUND. Noninvasive prenatal testing can be used to accurately detect chromosomal aneuploidies in circulating fetal DNA; however, the necessity of parental haplotype construction is a primary drawback to noninvasive prenatal diagnosis (NIPD) of monogenic disease. Family-specific haplotype assembly is essential for accurate diagnosis of minuscule amounts of circulating cell-free fetal DNA; however, current haplotyping techniques are too time-consuming and laborious to be carried out within the limited time constraints of prenatal testing, hampering practical application of NIPD in the clinic. Here, we have addressed this pitfall and devised a universal strategy for rapid NIPD of a prevalent mutation in the Ashkenazi Jewish (AJ) population. METHODS. Pregnant AJ couples, carrying mutation(s) in GBA, which encodes acid β-glucosidase, were recruited at the SZMC Gaucher Clinic. Targeted next-generation sequencing of GBA-flanking SNPs was performed on peripheral blood samples from each couple, relevant mutation carrier family members, and unrelated individuals who are homozygotes for an AJ founder mutation. Allele-specific haplotypes were constructed based on linkage, and a consensus Gaucher disease–associated founder mutation–flanking haplotype was fine mapped. Together, these haplotypes were used for NIPD. All test results were validated by conventional prenatal or postnatal diagnostic methods. RESULTS. Ten parental alleles in eight unrelated fetuses were diagnosed successfully based on the noninvasive method developed in this study. The consensus mutation–flanking haplotype aided diagnosis for 6 of 9 founder mutation alleles. CONCLUSIONS. The founder NIPD method developed and described here is rapid, economical, and readily adaptable for prenatal testing of prevalent autosomal recessive disease-causing mutations in an assortment of worldwide populations. FUNDING. SZMC, Protalix Biotherapeutics Inc., and Centogene AG. PMID:26426075

  13. Twin Town in South Brazil: A Nazi's Experiment or a Genetic Founder Effect?

    PubMed Central

    Tagliani-Ribeiro, Alice; Oliveira, Mariana; Sassi, Adriana K.; Rodrigues, Maira R.; Zagonel-Oliveira, Marcelo; Steinman, Gary; Matte, Ursula; Fagundes, Nelson J. R.; Schuler-Faccini, Lavinia

    2011-01-01

    Cândido Godói (CG) is a small municipality in South Brazil with approximately 6,000 inhabitants. It is known as the “Twins' Town” due to its high rate of twin births. Recently it was claimed that such high frequency of twinning would be connected to experiments performed by the German Nazi doctor Joseph Mengele. It is known, however, that this town was founded by a small number of families and therefore a genetic founder effect may represent an alternatively explanation for the high twinning prevalence in CG. In this study, we tested specific predictions of the “Nazi's experiment” and of the “founder effect” hypotheses. We surveyed a total of 6,262 baptism records from 1959–2008 in CG catholic churches, and identified 91 twin pairs and one triplet. Contrary to the “Nazi's experiment hypothesis”, there is no spurt in twinning between the years (1964–1968) when Mengele allegedly was in CG (P = 0.482). Moreover, there is no temporal trend for a declining rate of twinning since the 1960s (P = 0.351), and no difference in twinning among CG districts considering two different periods: 1927–1958 and 1959–2008 (P = 0.638). On the other hand, the “founder effect hypothesis” is supported by an isonymy analysis that shows that women who gave birth to twins have a higher inbreeding coefficient when compared to women who never had twins (0.0148, 0.0081, respectively, P = 0.019). In summary, our results show no evidence for the “Nazi's experiment hypothesis” and strongly suggest that the “founder effect hypothesis” is a much more likely alternative for explaining the high prevalence of twinning in CG. If this hypothesis is correct, then this community represents a valuable population where genetic factors linked to twinning may be identified. PMID:21687665

  14. Twin Town in South Brazil: a Nazi's experiment or a genetic founder effect?

    PubMed

    Tagliani-Ribeiro, Alice; Oliveira, Mariana; Sassi, Adriana K; Rodrigues, Maira R; Zagonel-Oliveira, Marcelo; Steinman, Gary; Matte, Ursula; Fagundes, Nelson J R; Schuler-Faccini, Lavinia

    2011-01-01

    Cândido Godói (CG) is a small municipality in South Brazil with approximately 6,000 inhabitants. It is known as the "Twins' Town" due to its high rate of twin births. Recently it was claimed that such high frequency of twinning would be connected to experiments performed by the German Nazi doctor Joseph Mengele. It is known, however, that this town was founded by a small number of families and therefore a genetic founder effect may represent an alternatively explanation for the high twinning prevalence in CG. In this study, we tested specific predictions of the "Nazi's experiment" and of the "founder effect" hypotheses. We surveyed a total of 6,262 baptism records from 1959-2008 in CG catholic churches, and identified 91 twin pairs and one triplet. Contrary to the "Nazi's experiment hypothesis", there is no spurt in twinning between the years (1964-1968) when Mengele allegedly was in CG (P = 0.482). Moreover, there is no temporal trend for a declining rate of twinning since the 1960s (P = 0.351), and no difference in twinning among CG districts considering two different periods: 1927-1958 and 1959-2008 (P = 0.638). On the other hand, the "founder effect hypothesis" is supported by an isonymy analysis that shows that women who gave birth to twins have a higher inbreeding coefficient when compared to women who never had twins (0.0148, 0.0081, respectively, P = 0.019). In summary, our results show no evidence for the "Nazi's experiment hypothesis" and strongly suggest that the "founder effect hypothesis" is a much more likely alternative for explaining the high prevalence of twinning in CG. If this hypothesis is correct, then this community represents a valuable population where genetic factors linked to twinning may be identified. PMID:21687665

  15. Ancient founder mutation is responsible for Imerslund-Gräsbeck Syndrome among diverse ethnicities

    PubMed Central

    2011-01-01

    Background Imerslund-Gräsbeck syndrome (IGS) was described just over 50 years ago by Olga Imerslund and Ralph Gräsbeck and colleagues. IGS is caused by specific malabsorption of cobalamin (Cbl) due to bi-allelic mutations in either the cubilin gene (CUBN) or the human amnionless homolog (AMN). Mutations in the two genes are commonly seen in founder populations or in societies with a high degree of consanguineous marriages. One particular mutation in AMN, c.208-2A>G, causing an out-of-frame loss of exon 4 in the mRNA, is responsible for some 15% of IGS cases globally. We present evidence that this founder mutation causes a substantial percentage of cases among diverse ethnicities and that the mutation is as old as human civilization. Methods Partial genotyping indicated a founder event but its presence in diverse peoples of Arabic, Turkish, Jewish, and Hispanic ancestry suggested that the mutation might be recurrent. We therefore studied the flanking sequence spanning 3.5 Mb to elucidate the origin of the haplotype and estimate the age of the mutation using a Bayesian inference method based on observed linkage disequilibrium. Results The mutation's distribution, the size of the shared haplotype, and estimates of growth rate and carrier frequency indicated that the mutation was a single prehistoric event. Dating back to the ancient Middle East around 11,600 BC, the mutation predates the advent of writing, farming, and the monotheistic religions of the region. Conclusions This mutation causes over 50% of the IGS cases among Arabic, Turkish, and Sephardic Jewish families, making it a primary target for genetic screening among diverse IGS cases originating from the Middle East. Thus, rare founder mutations may cause a substantial number of cases, even among diverse ethnicities not usually thought to be related. PMID:22078000

  16. A mitochondrial analysis reveals distinct founder effect signatures in Canarian and Balearic goats.

    PubMed

    Ferrando, A; Manunza, A; Jordana, J; Capote, J; Pons, A; Pais, J; Delgado, T; Atoche, P; Cabrera, B; Martínez, A; Landi, V; Delgado, J V; Argüello, A; Vidal, O; Lalueza-Fox, C; Ramírez, O; Amills, M

    2015-08-01

    In the course of human migrations, domestic animals often have been translocated to islands with the aim of assuring food availability. These founder events are expected to leave a genetic footprint that may be recognised nowadays. Herewith, we have examined the mitochondrial diversity of goat populations living in the Canarian and Balearic archipelagos. Median-joining network analysis produced very distinct network topologies for these two populations. Indeed, a majority of Canarian goats shared a single ancestral haplotype that segregated in all sampled islands, suggesting a single founder effect followed by a stepping-stone pattern of diffusion. This haplotype also was present in samples collected from archaeological assemblies at Gran Canaria and Lanzarote, making evident its widespread distribution in ancient times. In stark contrast, goats from Majorca and Ibiza did not share any mitochondrial haplotypes, indicating the occurrence of two independent founder events. Furthermore, in Majorcan goats, we detected the segregation of the mitochondrial G haplogroup that has only been identified in goats from Egypt, Iran and Turkey. This finding suggests the translocation of Asian and/or African goats to Majorca, possibly as a consequence of the Phoenician and Carthaginian colonisations of this island. PMID:26153924

  17. The Sex Determination Gene Shows No Founder Effect in the Giant Honey Bee, Apis dorsata

    PubMed Central

    Yan, Wei Yu; Wu, Xiao Bo; Zeng, Zhi Jiang; Huang, Zachary Y.

    2012-01-01

    Background All honey bee species (Apis spp) share the same sex determination mechanism using the complementary sex determination (csd) gene. Only individuals heterogeneous at the csd allele develop into females, and the homozygous develop into diploid males, which do not survive. The honeybees are therefore under selection pressure to generate new csd alleles. Previous studies have shown that the csd gene is under balancing selection. We hypothesize that due to the long separation from the mainland of Hainan Island, China, that the giant honey bees (Apis dorsata) should show a founder effect for the csd gene, with many different alleles clustered together, and these would be absent on the mainland. Methodology/Principal Findings We sampled A. dorsata workers from both Hainan and Guangxi Provinces and then cloned and sequenced region 3 of the csd gene and constructed phylogenetic trees. We failed to find any clustering of the csd alleles according to their geographical origin, i.e. the Hainan and Guangxi samples did not form separate clades. Further analysis by including previously published csd sequences also failed to show any clade-forming in both the Philippines and Malaysia. Conclusions/Significance Results from this study and those from previous studies did not support the expectations of a founder effect. We conclude that because of the extremely high mating frequency of A. dorsata queens, a founder effect does not apply in this species. PMID:22511940

  18. 76 FR 35263 - Founders Equity SBIC I, L.P.; Notice Seeking Exemption Under Section 312 of the Small Business...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-16

    ... Investment Act, Conflicts of Interest Notice is hereby given that Founders Equity SBIC I, L.P., 711 Fifth... exemption under Section 312 of the Act and Section 107.730, Financings Which Constitute Conflicts...

  19. Differences in the Selection Bottleneck between Modes of Sexual Transmission Influence the Genetic Composition of the HIV-1 Founder Virus.

    PubMed

    Tully, Damien C; Ogilvie, Colin B; Batorsky, Rebecca E; Bean, David J; Power, Karen A; Ghebremichael, Musie; Bedard, Hunter E; Gladden, Adrianne D; Seese, Aaron M; Amero, Molly A; Lane, Kimberly; McGrath, Graham; Bazner, Suzane B; Tinsley, Jake; Lennon, Niall J; Henn, Matthew R; Brumme, Zabrina L; Norris, Philip J; Rosenberg, Eric S; Mayer, Kenneth H; Jessen, Heiko; Kosakovsky Pond, Sergei L; Walker, Bruce D; Altfeld, Marcus; Carlson, Jonathan M; Allen, Todd M

    2016-05-01

    Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic "signatures" within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission. PMID:27163788

  20. Differences in the Selection Bottleneck between Modes of Sexual Transmission Influence the Genetic Composition of the HIV-1 Founder Virus

    PubMed Central

    Tully, Damien C.; Ogilvie, Colin B.; Batorsky, Rebecca E.; Bean, David J.; Power, Karen A.; Ghebremichael, Musie; Bedard, Hunter E.; Gladden, Adrianne D.; Seese, Aaron M.; Amero, Molly A.; Lane, Kimberly; McGrath, Graham; Bazner, Suzane B.; Tinsley, Jake; Lennon, Niall J.; Henn, Matthew R.; Brumme, Zabrina L.; Norris, Philip J.; Rosenberg, Eric S.; Mayer, Kenneth H.; Jessen, Heiko; Kosakovsky Pond, Sergei L.; Walker, Bruce D.; Altfeld, Marcus; Carlson, Jonathan M.; Allen, Todd M.

    2016-01-01

    Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic “signatures” within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission. PMID:27163788

  1. Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene

    PubMed Central

    Sarkozy, Anna; Windpassinger, Christian; Hudson, Judith; Dougan, Charlotte F; Lecky, Bryan; Hilton-Jones, David; Eagle, Michelle; Charlton, Richard; Barresi, Rita; Lochmüller, Hanns; Bushby, Kate; Straub, Volker

    2011-01-01

    Mutations in the four-and-a-half LIM domain 1 (FHL1) gene, which encodes a 280-amino-acid protein containing four LIM domains and a single zinc-finger domain in the N-terminal region, have been associated with a broad clinical spectrum of X-linked muscle diseases encompassing a variety of different phenotypes. Patients might present with a scapuloperoneal myopathy, a myopathy with postural muscle atrophy and generalized hypertrophy, an Emery–Dreifuss muscular dystrophy, or an early onset myopathy with reducing bodies. It has been proposed that the phenotypic variability is related to the position of the mutation within the FHL1 gene. Here, we report on three British families with a heterogeneous clinical presentation segregating a single FHL1 gene mutation and haplotype, suggesting that this represents a founder mutation. The underlying FHL1 gene mutation was detected by direct sequencing and the founder effect was verified by haplotype analysis of the FHL1 gene locus. A 3-bp insertion mutation (p.Phe127_Thr128insIle) within the second LIM domain of the FHL1 gene was identified in all available affected family members of the three families. Haplotype analysis of the FHL1 region on Xq26 revealed that the families shared a common haplotype. The p.Phe127_Thr128insIle mutation in the FHL1 gene therefore appears to be a British founder mutation and FHL1 gene screening, in particular of exon 6, should therefore be indicated in British patients with a broad phenotypic spectrum of X-linked muscle diseases. PMID:21629301

  2. Muir-Torre Syndrome and founder mismatch repair gene mutations: A long gone historical genetic challenge.

    PubMed

    Ponti, G; Manfredini, M; Tomasi, A; Pellacani, G

    2016-09-10

    A "cancer predisposing syndrome" later labeled as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch Syndrome, was firstly described by Warthin, about one century ago. An increased predisposition to the development of multiple familial tumors is described as characteristic of this syndrome where visceral and cutaneous malignancies may appear at an early age namely endometrial, gastric, small bowel, ureteral and renal pelvis, ovarian, hepatobiliary tract, pancreatic, brain (Turcot Syndrome) and sebaceous glands (Muir-Torre Syndrome). The latter, a variant of Lynch Syndrome, is characterized by the presence of sebaceous skin adenomas, carcinomas and/or keratoacanthomas associated with visceral malignancies. Both Lynch Syndrome and Muir-Torre Syndrome have been recognized due to germline mutations in mismatch repair genes MLH1, MSH2 and MSH6. To date, 56 Lynch Syndrome founder mutations dependent on MLH1, MSH2 and, although less frequently found, MSH6 and PMS2 are described. Some of these founder mutations, principally of MSH2 gene, have been described to cause Muir-Torre phenotype and have been traced in large and outbreed Muir-Torre Syndrome families living in different US and European territories. Due to the evidences of highly specific Muir-Torre phenotypes related to the presence of widespread MSH2 founder mutations, preliminary search for these MSH2 common mutations in individuals carrying sebaceous tumors and/or keratoacanthomas, at early age or in association to visceral and familial tumors, permits cost-effective and time-saving diagnostic strategies for Lynch/Muir-Torre Syndromes. PMID:26143115

  3. Tracing European Founder Lineages in the Near Eastern mtDNA Pool

    PubMed Central

    Richards, Martin; Macaulay, Vincent; Hickey, Eileen; Vega, Emilce; Sykes, Bryan; Guida, Valentina; Rengo, Chiara; Sellitto, Daniele; Cruciani, Fulvio; Kivisild, Toomas; Villems, Richard; Thomas, Mark; Rychkov, Serge; Rychkov, Oksana; Rychkov, Yuri; Gölge, Mukaddes; Dimitrov, Dimitar; Hill, Emmeline; Bradley, Dan; Romano, Valentino; Calì, Francesco; Vona, Giuseppe; Demaine, Andrew; Papiha, Surinder; Triantaphyllidis, Costas; Stefanescu, Gheorghe; Hatina, Jiři; Belledi, Michele; Di Rienzo, Anna; Oppenheim, Ariella; Nørby, Søren; Al-Zaheri, Nadia; Santachiara-Benerecetti, Silvana; Scozzari, Rosaria; Torroni, Antonio; Bandelt, Hans-Jürgen

    2000-01-01

    Founder analysis is a method for analysis of nonrecombining DNA sequence data, with the aim of identification and dating of migrations into new territory. The method picks out founder sequence types in potential source populations and dates lineage clusters deriving from them in the settlement zone of interest. Here, using mtDNA, we apply the approach to the colonization of Europe, to estimate the proportion of modern lineages whose ancestors arrived during each major phase of settlement. To estimate the Palaeolithic and Neolithic contributions to European mtDNA diversity more accurately than was previously achievable, we have now extended the Near Eastern, European, and northern-Caucasus databases to 1,234, 2,804, and 208 samples, respectively. Both back-migration into the source population and recurrent mutation in the source and derived populations represent major obstacles to this approach. We have developed phylogenetic criteria to take account of both these factors, and we suggest a way to account for multiple dispersals of common sequence types. We conclude that (i) there has been substantial back-migration into the Near East, (ii) the majority of extant mtDNA lineages entered Europe in several waves during the Upper Palaeolithic, (iii) there was a founder effect or bottleneck associated with the Last Glacial Maximum, 20,000 years ago, from which derives the largest fraction of surviving lineages, and (iv) the immigrant Neolithic component is likely to comprise less than one-quarter of the mtDNA pool of modern Europeans. PMID:11032788

  4. Andrew Sexton Gray (1826-1907). A founder of Australian ophthalmology: his life and times.

    PubMed

    Lowe, R F

    1985-11-01

    Andrew Sexton Gray was born in Limerick, Ireland, medically trained in Dublin, and was assistant to William Wilde, the distinguished oculist and aurist. He migrated to Victoria in 1859, was surgeon to a railway's construction company, then in 1862 began practice as a surgeon and oculist in Melbourne. In 1863 he founded a charitable eye and ear hospital, and had a very active, long life devoted mostly to ophthalmology. The hospital progressively expanded and became the centre for training for many ophthalmologists, as well as the nucleus for the cohesion of Victorian ophthalmology. History shows Andrew Sexton Gray to have been a founder of Australian ophthalmology. PMID:3914312

  5. Trench-parallel anisotropy produced by foundering of arc lower crust.

    PubMed

    Behn, Mark D; Hirth, Greg; Kelemen, Peter B

    2007-07-01

    Many volcanic arcs display fast seismic shear-wave velocities parallel to the strike of the trench. This pattern of anisotropy is inconsistent with simple models of corner flow in the mantle wedge. Although several models, including slab rollback, oblique subduction, and deformation of water-rich olivine, have been proposed to explain trench-parallel anisotropy, none of these mechanisms are consistent with all observations. Instead, small-scale convection driven by the foundering of dense arc lower crust provides an explanation for the trench-parallel anisotropy, even in settings with orthogonal convergence and no slab rollback. PMID:17615354

  6. Genetically diverse CC-founder mouse strains replicate the human influenza gene expression signature

    PubMed Central

    Elbahesh, Husni; Schughart, Klaus

    2016-01-01

    Influenza A viruses (IAV) are zoonotic pathogens that pose a major threat to human and animal health. Influenza virus disease severity is influenced by viral virulence factors as well as individual differences in host response. We analyzed gene expression changes in the blood of infected mice using a previously defined set of signature genes that was derived from changes in the blood transcriptome of IAV-infected human volunteers. We found that the human signature was reproduced well in the founder strains of the Collaborative Cross (CC) mice, thus demonstrating the relevance and importance of mouse experimental model systems for studying human influenza disease. PMID:27193691

  7. Genetically diverse CC-founder mouse strains replicate the human influenza gene expression signature.

    PubMed

    Elbahesh, Husni; Schughart, Klaus

    2016-01-01

    Influenza A viruses (IAV) are zoonotic pathogens that pose a major threat to human and animal health. Influenza virus disease severity is influenced by viral virulence factors as well as individual differences in host response. We analyzed gene expression changes in the blood of infected mice using a previously defined set of signature genes that was derived from changes in the blood transcriptome of IAV-infected human volunteers. We found that the human signature was reproduced well in the founder strains of the Collaborative Cross (CC) mice, thus demonstrating the relevance and importance of mouse experimental model systems for studying human influenza disease. PMID:27193691

  8. [Professor He Pu-ren: the founder of Santong method of acupuncture and moxibustion].

    PubMed

    Wang, Lin-peng; Xie, Xin-cai; He, Chang; Cheng, Hai-ying; Xu, Chun-yang; Wang, Jing-xi; Zhang, Xin-yue; Wang, Gui-ling; He, Xiao-jing

    2009-02-01

    Professor He Pu-ren, the founder of Santong method of acupuncture and moxibustion, is a well known acupuncturist at home and abroad. His main contributions include combined martial arts and Chinese medicine, showing obvious therapeutic effect; taking part in establishment of The Department of Acupuncture, Beijing Chinese Medicine Hospital; creating Santong method of acupuncture and moxibustion; advocating fire needle therapy; writing medical books and teaching students; advocating the culture of acupuncture; making the metal model of acupuncture and moxibustion, and others. His achievements have become an important part of acupuncture and moxibustion science. PMID:19391541

  9. Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer?

    PubMed

    Lener, Marcin R; Scott, Rodney J; Kluźniak, Wojciech; Baszuk, Piotr; Cybulski, Cezary; Wiechowska-Kozłowska, Anna; Huzarski, Tomasz; Byrski, Tomasz; Kładny, Józef; Pietrzak, Sandra; Soluch, Agnieszka; Jakubowska, Anna; Lubiński, Jan

    2016-08-01

    Understanding of the etiology and risk of pancreatic cancer (PaCa) is still poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in four genes among PaCa patients and assessed their possible association with the risk of disease in Poland. In the study 383 PaCa patients and 4,000 control subjects were genotyped for founder mutations in: BRCA1 (5382insC, 4153delA, C61G), CHEK2 (1100delC, IVS2 + 1G > A, del5395, I157T), NBS1 (657del5) and PALB2 (509_510delGA, 172_175delTTGT). A statistically significant association between the 657del5 mutation and an increased risk of pancreatic cancer was observed for NBS1 gene. The Slavic NBS1 gene mutation (657delACAAA) was detected in 8 of 383 (2.09%) unselected cases compared with 22 of 4,000 (0.55%) controls (OR: 3.80, p = 0.002). The PALB2 509_510delGA and 172_175delTTGT mutations combined were seen in 2 (0.52%) unselected cases of PaCa and in 8 (0.20%) of 4,000 controls (OR: 2.61, p = 0.49). For BRCA1, the three mutations combined were detected in 4 of 383 (1.04%) PaCa patients and in 17 of 4,000 (0.42%) controls (OR: 2.46, p = 0.20). CHEK2 mutations were not associated with the risk of pancreatic cancer (OR: 1.11, p = 0.72). The founder mutation in NBS1 (657del5) was associated with an increased risk of PaCa in heterozygous carriers, indicating that this mutation appears to predispose to cancer of the pancreas. By identifying pancreatic cancer risk groups, founder mutation testing in Poland should be considered for people at risk for PaCa. PMID:27038244

  10. Birth of scientific surgery. John Hunter versus Joseph Lister as the father or founder of scientific surgery.

    PubMed

    Toledo-Pereyra, Luis H

    2010-02-01

    John Hunter (1728-1793) has frequently been considered the "Father or Founder of Scientific Surgery". His inscription at Westminster Abbey presents him as "a gifted interpreter of the Divine Power and wisdom at work in the laws of organic life and the Founder of Scientific Surgery." I take issue with Hunter being considered the father or founder of scientific surgery and propose Joseph Lister (1827-1912) as the one who should receive this consideration. Hunter was a skilled surgeon, an inquisitive innovator, keen observer, great naturalist, and astute thinker, who made no surgical discoveries of any transcendence to the discipline. His scientific observations were not in the field of surgery. Therefore, he should not be considered the "Father or Founder of Scientific Surgery." On the contrary, Lister became a revolutionary scientific innovator by explaining the pervasive role of microorganisms in surgical wounds. His work directly affected surgery and its role in medicine. Lister, therefore, should be considered the "Father or Founder of Scientific Surgery." PMID:20232999

  11. Serial founder effects and genetic differentiation during worldwide range expansion of monarch butterflies

    PubMed Central

    Pierce, Amanda A.; Zalucki, Myron P.; Bangura, Marie; Udawatta, Milan; Kronforst, Marcus R.; Altizer, Sonia; Haeger, Juan Fernández; de Roode, Jacobus C.

    2014-01-01

    Range expansions can result in founder effects, increasing genetic differentiation between expanding populations and reducing genetic diversity along the expansion front. However, few studies have addressed these effects in long-distance migratory species, for which high dispersal ability might counter the effects of genetic drift. Monarchs (Danaus plexippus) are best known for undertaking a long-distance annual migration in North America, but have also dispersed around the world to form populations that do not migrate or travel only short distances. Here, we used microsatellite markers to assess genetic differentiation among 18 monarch populations and to determine worldwide colonization routes. Our results indicate that North American monarch populations connected by land show limited differentiation, probably because of the monarch's ability to migrate long distances. Conversely, we found high genetic differentiation between populations separated by large bodies of water. Moreover, we show evidence for serial founder effects across the Pacific, suggesting stepwise dispersal from a North American origin. These findings demonstrate that genetic drift played a major role in shaping allele frequencies and created genetic differentiation among newly formed populations. Thus, range expansion can give rise to genetic differentiation and declines in genetic diversity, even in highly mobile species. PMID:25377462

  12. Founder effect and prevalence of myotonic dystrophy in South Africans: molecular studies.

    PubMed Central

    Goldman, A.; Krause, A.; Ramsay, M.; Jenkins, T.

    1996-01-01

    A high prevalence of myotonic dystrophy (DM) has been described in South African Caucasoid Afrikaans-speaking families in the northern Transvaal. Evidence is presented for a strong founder effect, with a single haplotype occurring on 68% of all Caucasoid DM chromosomes; among the Afrikaans speakers, the proportion was 83%. In addition to this major haplotype, five minor DM haplotypes in the Caucasoids and two minor haplotypes in DM individuals of mixed ancestry were found. All DM chromosomes, however, had a common haplotype core, namely, Alu (ins), HinfI-2 (intron 9), and TaqI-2 (D19S463). We have detected significant linkage disequilibrium between the DM mutation and particular alleles of the extragenic markers D19S112 and D19S207. Significant differences were found in allele and haplotype distributions in the Caucasoid DM and non-DM chromosomes and Negroid non-DM chromosomes. These findings together with the strong association of allele 3 at the D19S63 locus on 93% (14/15) of the South African DM chromosomes suggest that the majority of present-day DM mutations in South African Caucasoids may have originated from a common initial founder who introduced one of the European ancestral mutations. PMID:8755933

  13. PRIMAL: Fast and Accurate Pedigree-based Imputation from Sequence Data in a Founder Population

    PubMed Central

    Livne, Oren E.; Han, Lide; Alkorta-Aranburu, Gorka; Wentworth-Sheilds, William; Abney, Mark; Ober, Carole; Nicolae, Dan L.

    2015-01-01

    Founder populations and large pedigrees offer many well-known advantages for genetic mapping studies, including cost-efficient study designs. Here, we describe PRIMAL (PedigRee IMputation ALgorithm), a fast and accurate pedigree-based phasing and imputation algorithm for founder populations. PRIMAL incorporates both existing and original ideas, such as a novel indexing strategy of Identity-By-Descent (IBD) segments based on clique graphs. We were able to impute the genomes of 1,317 South Dakota Hutterites, who had genome-wide genotypes for ~300,000 common single nucleotide variants (SNVs), from 98 whole genome sequences. Using a combination of pedigree-based and LD-based imputation, we were able to assign 87% of genotypes with >99% accuracy over the full range of allele frequencies. Using the IBD cliques we were also able to infer the parental origin of 83% of alleles, and genotypes of deceased recent ancestors for whom no genotype information was available. This imputed data set will enable us to better study the relative contribution of rare and common variants on human phenotypes, as well as parental origin effect of disease risk alleles in >1,000 individuals at minimal cost. PMID:25735005

  14. Rapid and efficient analysis of gene function using CRISPR-Cas9 in Xenopus tropicalis founders.

    PubMed

    Shigeta, Mitsuki; Sakane, Yuto; Iida, Midori; Suzuki, Miyuki; Kashiwagi, Keiko; Kashiwagi, Akihiko; Fujii, Satoshi; Yamamoto, Takashi; Suzuki, Ken-Ichi T

    2016-07-01

    Recent advances in genome editing using programmable nucleases, such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system, have facilitated reverse genetics in Xenopus tropicalis. To establish a practical workflow for analyzing genes of interest using CRISPR-Cas9, we examined various experimental procedures and conditions. We first compared the efficiency of gene disruption between Cas9 protein and mRNA injection by analyzing genotype and phenotype frequency, and toxicity. Injection of X. tropicalis embryos with Cas9 mRNA resulted in high gene-disrupting efficiency comparable with that produced by Cas9 protein injection. To exactly evaluate the somatic mutation rates of on-target sites, amplicon sequencing and restriction fragment length polymorphism analysis using a restriction enzyme or recombinant Cas9 were performed. Mutation rates of two target genes (slc45a2 and ltk) required for pigmentation were estimated to be over 90% by both methods in animals exhibiting severe phenotypes, suggesting that targeted somatic mutations were biallelically introduced in almost all somatic cells of founder animals. Using a heteroduplex mobility assay, we also showed that off-target mutations were induced at a low rate. Based on our results, we propose a CRISPR-Cas9-mediated gene disruption workflow for a rapid and efficient analysis of gene function using X. tropicalis founders. PMID:27219625

  15. Mitochondrial DNA analysis of an immigrant Basque population: loss of diversity due to founder effects.

    PubMed

    Davis, Michael C; Novak, Stephen J; Hampikian, Greg

    2011-04-01

    The Basques have a well-documented history of migration and settlement in the Americas, and they often retain cultural identity across generations. Numerous genetic studies have been carried out on European Basques; thus, immigrant Basques are an ideal population for investigating the genetic consequences of a recent human migration event. We have sampled 53 unrelated individuals with Basque ancestry in Boise, Idaho and determined the mitochondrial DNA (mtDNA) sequence variation of the first and second hypervariable regions. Thirty-six mtDNA haplotypes were detected in our sample. We found evidence of genetic changes consistent with founder effects, which is compatible with the known history of migration. Compared with the European Basque population, the immigrant Basques are significantly different in terms of haplogroup frequency distribution and diversity. They have a lower measure of weighted intralineage mean pairwise diversity (WIMP) and greater genetic distance from other European populations. These data indicate that this immigrant Basque population has experienced a reduction in genetic diversity compared with the putative source population. However, this loss of diversity is not detectable using indices of demographic history such as Tajima's D and Fu's F. This study represents the first description of mtDNA diversity in an immigrant Basque population, and our findings indicate that founder effects accompanying this relatively recent migration event have shaped the genetic diversity of this population. PMID:21404229

  16. Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families.

    PubMed Central

    Tonin, P N; Mes-Masson, A M; Futreal, P A; Morgan, K; Mahon, M; Foulkes, W D; Cole, D E; Provencher, D; Ghadirian, P; Narod, S A

    1998-01-01

    We have identified four mutations in each of the breast cancer-susceptibility genes, BRCA1 and BRCA2, in French Canadian breast cancer and breast/ovarian cancer families from Quebec. To identify founder effects, we examined independently ascertained French Canadian cancer families for the distribution of these eight mutations. Mutations were found in 41 of 97 families. Six of eight mutations were observed at least twice. The BRCA1 C4446T mutation was the most common mutation found, followed by the BRCA2 8765delAG mutation. Together, these mutations were found in 28 of 41 families identified to have a mutation. The odds of detection of any of the four BRCA1 mutations was 18.7x greater if one or more cases of ovarian cancer were also present in the family. The odds of detection of any of the four BRCA2 mutations was 5.3x greater if there were at least five cases of breast cancer in the family. Interestingly, the presence of a breast cancer case <36 years of age was strongly predictive of the presence of any of the eight mutations screened. Carriers of the same mutation, from different families, shared similar haplotypes, indicating that the mutant alleles were likely to be identical by descent for a mutation in the founder population. The identification of common BRCA1 and BRCA2 mutations will facilitate carrier detection in French Canadian breast cancer and breast/ovarian cancer families. PMID:9792861

  17. Mutational founder effect in recessive dystrophic epidermolysis bullosa families from Southern Tunisia.

    PubMed

    Ben Brick, Ahlem Sabrine; Laroussi, Nadia; Mesrati, Hela; Kefi, Rym; Bchetnia, Mbarka; Lasram, Khaled; Ben Halim, Nizar; Romdhane, Lilia; Ouragini, Houyem; Marrakchi, Salaheddine; Boubaker, Mohamed Samir; Meddeb Cherif, Mounira; Castiglia, Daniele; Hovnanian, Alain; Abdelhak, Sonia; Turki, Hamida

    2014-05-01

    Dystrophic epidermolysis bullosa (DEB) is a group of heritable bullous skin disorders caused by mutations in the COL7A1 gene. One of the most severe forms of DEB is the severe generalized [recessive dystrophic epidermolysis bullosa (RDEB-SG)] subtype, which is inherited in an autosomal recessive manner. This subtype is most often due to COL7A1 mutations resulting in a premature termination codon on both alleles. We report here, the molecular investigation of 15 patients belonging to 14 nuclear families from the city of Sfax in Southern Tunisia, with clinical features of RDEB-SG complicated by squamous cell carcinoma in 3 patients. We identified two novel mutations, p.Val769LeufsX1 and p.Ala2297SerfsX91, in addition to one previously reported mutation (p.Arg2063Trp). The p.Val769LeufsX1 mutation was shared by 11 families and haplotype analysis indicated that it is a founder mutation. The p.Ala2297SerfsX91 mutation was a private mutation found in only one family. Together with the previously described recurrent mutations in Tunisia, screening for the founder p.Val769LeufsX1 mutation should provide a rapid molecular diagnosis tool for mutation screening in RDEB patients from Southern Tunisia and possibly from other Mediterranean populations sharing the same genetic background. PMID:24170138

  18. Can a linguistic serial founder effect originating in Africa explain the worldwide phonemic cline?

    PubMed

    Fort, Joaquim; Pérez-Losada, Joaquim

    2016-04-01

    It has been proposed that a serial founder effect could have caused the present observed pattern of global phonemic diversity. Here we present a model that simulates the human range expansion out of Africa and the subsequent spatial linguistic dynamics until today. It does not assume copying errors, Darwinian competition, reduced contrastive possibilities or any other specific linguistic mechanism. We show that the decrease of linguistic diversity with distance (from the presumed origin of the expansion) arises under three assumptions, previously introduced by other authors: (i) an accumulation rate for phonemes; (ii) small phonemic inventories for the languages spoken before the out-of-Africa dispersal; (iii) an increase in the phonemic accumulation rate with the number of speakers per unit area. Numerical simulations show that the predictions of the model agree with the observed decrease of linguistic diversity with increasing distance from the most likely origin of the out-of-Africa dispersal. Thus, the proposal that a serial founder effect could have caused the present observed pattern of global phonemic diversity is viable, if three strong assumptions are satisfied. PMID:27122180

  19. Serial founder effects and genetic differentiation during worldwide range expansion of monarch butterflies.

    PubMed

    Pierce, Amanda A; Zalucki, Myron P; Bangura, Marie; Udawatta, Milan; Kronforst, Marcus R; Altizer, Sonia; Haeger, Juan Fernández; de Roode, Jacobus C

    2014-12-22

    Range expansions can result in founder effects, increasing genetic differentiation between expanding populations and reducing genetic diversity along the expansion front. However, few studies have addressed these effects in long-distance migratory species, for which high dispersal ability might counter the effects of genetic drift. Monarchs (Danaus plexippus) are best known for undertaking a long-distance annual migration in North America, but have also dispersed around the world to form populations that do not migrate or travel only short distances. Here, we used microsatellite markers to assess genetic differentiation among 18 monarch populations and to determine worldwide colonization routes. Our results indicate that North American monarch populations connected by land show limited differentiation, probably because of the monarch's ability to migrate long distances. Conversely, we found high genetic differentiation between populations separated by large bodies of water. Moreover, we show evidence for serial founder effects across the Pacific, suggesting stepwise dispersal from a North American origin. These findings demonstrate that genetic drift played a major role in shaping allele frequencies and created genetic differentiation among newly formed populations. Thus, range expansion can give rise to genetic differentiation and declines in genetic diversity, even in highly mobile species. PMID:25377462

  20. Role of founder cell deficit and delayed neuronogenesis in microencephaly of the trisomy 16 mouse

    NASA Technical Reports Server (NTRS)

    Haydar, T. F.; Nowakowski, R. S.; Yarowsky, P. J.; Krueger, B. K.

    2000-01-01

    Development of the neocortex of the trisomy 16 (Ts16) mouse, an animal model of Down syndrome (DS), is characterized by a transient delay in the radial expansion of the cortical wall and a persistent reduction in cortical volume. Here we show that at each cell cycle during neuronogenesis, a smaller proportion of Ts16 progenitors exit the cell cycle than do control, euploid progenitors. In addition, the cell cycle duration was found to be longer in Ts16 than in euploid progenitors, the Ts16 growth fraction was reduced, and an increase in apoptosis was observed in both proliferative and postmitotic zones of the developing Ts16 neocortical wall. Incorporation of these changes into a model of neuronogenesis indicates that they are sufficient to account for the observed delay in radial expansion. In addition, the number of neocortical founder cells, i.e., precursors present just before neuronogenesis begins, is reduced by 26% in Ts16 mice, leading to a reduction in overall cortical size at the end of Ts16 neuronogenesis. Thus, altered proliferative characteristics during Ts16 neuronogenesis result in a delay in the generation of neocortical neurons, whereas the founder cell deficit leads to a proportional reduction in the overall number of neurons. Such prenatal perturbations in either the timing of neuron generation or the final number of neurons produced may lead to significant neocortical abnormalities such as those found in DS.

  1. Can a linguistic serial founder effect originating in Africa explain the worldwide phonemic cline?

    PubMed Central

    2016-01-01

    It has been proposed that a serial founder effect could have caused the present observed pattern of global phonemic diversity. Here we present a model that simulates the human range expansion out of Africa and the subsequent spatial linguistic dynamics until today. It does not assume copying errors, Darwinian competition, reduced contrastive possibilities or any other specific linguistic mechanism. We show that the decrease of linguistic diversity with distance (from the presumed origin of the expansion) arises under three assumptions, previously introduced by other authors: (i) an accumulation rate for phonemes; (ii) small phonemic inventories for the languages spoken before the out-of-Africa dispersal; (iii) an increase in the phonemic accumulation rate with the number of speakers per unit area. Numerical simulations show that the predictions of the model agree with the observed decrease of linguistic diversity with increasing distance from the most likely origin of the out-of-Africa dispersal. Thus, the proposal that a serial founder effect could have caused the present observed pattern of global phonemic diversity is viable, if three strong assumptions are satisfied. PMID:27122180

  2. Signatures of seaway closures and founder dispersal in the phylogeny of a circumglobally distributed seahorse lineage

    PubMed Central

    Teske, Peter R; Hamilton, Healy; Matthee, Conrad A; Barker, Nigel P

    2007-01-01

    Background The importance of vicariance events on the establishment of phylogeographic patterns in the marine environment is well documented, and generally accepted as an important cause of cladogenesis. Founder dispersal (i.e. long-distance dispersal followed by founder effect speciation) is also frequently invoked as a cause of genetic divergence among lineages, but its role has long been challenged by vicariance biogeographers. Founder dispersal is likely to be common in species that colonize remote habitats by means of rafting (e.g. seahorses), as long-distance dispersal events are likely to be rare and subsequent additional recruitment from the source habitat is unlikely. In the present study, the relative importance of vicariance and founder dispersal as causes of cladogenesis in a circumglobally distributed seahorse lineage was investigated using molecular dating. A phylogeny was reconstructed using sequence data from mitochondrial and nuclear markers, and the well-documented closure of the Central American seaway was used as a primary calibration point to test whether other bifurcations in the phylogeny could also have been the result of vicariance events. The feasibility of three other vicariance events was explored: a) the closure of the Indonesian Seaway, resulting in sister lineages associated with the Indian Ocean and West Pacific, respectively; b) the closure of the Tethyan Seaway, resulting in sister lineages associated with the Indo-Pacific and Atlantic Ocean, respectively, and c) continental break-up during the Mesozoic followed by spreading of the Atlantic Ocean, resulting in pairs of lineages with amphi-Atlantic distribution patterns. Results Comparisons of pairwise genetic distances among the seahorse species hypothesized to have diverged as a result of the closure of the Central American Seaway with those of published teleost sequences having the same distribution patterns show that the seahorses were among the last to diverge. This suggests

  3. PedHunter 2.0 and its usage to characterize the founder structure of the Old Order Amish of Lancaster County

    PubMed Central

    2010-01-01

    Background Because they are a closed founder population, the Old Order Amish (OOA) of Lancaster County have been the subject of many medical genetics studies. We constructed four versions of Anabaptist Genealogy Database (AGDB) using three sources of genealogies and multiple updates. In addition, we developed PedHunter, a suite of query software that can solve pedigree-related problems automatically and systematically. Methods We report on how we have used new features in PedHunter to quantify the number and expected genetic contribution of founders to the OOA. The queries and utility of PedHunter programs are illustrated by examples using AGDB in this paper. For example, we calculated the number of founders expected to be contributing genetic material to the present-day living OOA and estimated the mean relative founder representation for each founder. New features in PedHunter also include pedigree trimming and pedigree renumbering, which should prove useful for studying large pedigrees. Results With PedHunter version 2.0 querying AGDB version 4.0, we identified 34,160 presumed living OOA individuals and connected them into a 14-generation pedigree descending from 554 founders (332 females and 222 males) after trimming. From the analysis of cumulative mean relative founder representation, 128 founders (78 females and 50 males) accounted for over 95% of the mean relative founder contribution among living OOA descendants. Discussion/Conclusions The OOA are a closed founder population in which a modest number of founders account for the genetic variation present in the current OOA population. Improvements to the PedHunter software will be useful in future studies of both the OOA and other populations with large and computerized genealogies. PMID:20433770

  4. Associations of High-Grade Prostate Cancer with BRCA1 and BRCA2 Founder Mutations

    PubMed Central

    Agalliu, Ilir; Gern, Robert; Leanza, Suzanne; Burk, Robert D.

    2013-01-01

    Purpose Protein-truncating mutations in BRCA1 and in particular BRCA2 genes have been associated with prostate cancer. However, there is still uncertainty about the magnitude of association particularly with Gleason score, and family history of prostate, breast, and ovary cancers. Experimental Design To further examine associations between three founder mutations located in BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) genes and prostate cancer, we conducted a study of 979 prostate cancer cases and 1,251 controls among Ashkenazi Jewish men. Detailed information was obtained on prostate cancer pathology, age at diagnosis, and family history of all cancers. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression models. Results Prostate cancer risk was increased (OR, 1.9; 95% CI 0.9-4.1) for BRCA2 mutation carriers but not for BRCA1 mutation carriers. BRCA2 mutation carriers had an OR of 3.2 (95% CI, 1.4-7.3) for Gleason score of 7 to 10, but no association was observed for Gleason score of <7. Carriers of BRCA1-185delAG mutation also had an OR of 3.5 (95% CI, 1.2-10.3) for Gleason score of ≥7 tumors; however, the association of either BRCA1-185delAG or 5382insC mutation was not statistically significant. Associations between founder mutations and prostate cancer were stronger in men with no first-degree family history of breast and/or ovarian cancers but were unaffected by family history of prostate cancer. Conclusion These results indicate that the BRCA2 founder mutation confers a 3-fold elevated risk of high-grade prostate cancer. Although BRCA1 mutations were not associated with prostate cancer, the BRCA1-185delAG was associated with high Gleason score tumors. These findings should be carefully considered in genetic counseling and/or evaluating therapeutic options. PMID:19188187

  5. A Common Founder Mutation in the EDA-A1 Gene in X-Linked Hypodontia

    PubMed Central

    Kurban, Mazen; Michailidis, Eleni; Wajid, Muhammad; Shimomura, Yutaka; Christiano, Angela M.

    2010-01-01

    Background X-linked recessive hypohidrotic ectodermal dysplasia (XLHED; OMIM 305100) is a rare genodermatosis characterized clinically by developmental abnormalities affecting the teeth, hair and sweat glands. Mutations in the EDA-A1 gene have been associated with XLHED. Recently, mutations in the EDA-A1 gene have also been implicated in isolated X-linked recessive hypodontia (XLRH; OMIM 313500). Methods We analyzed the DNA from members of 3 unrelated Pakistani families with XLRH for mutations in the EDA-A1 gene through direct sequencing and performed haplotype analysis. Results We identified a common missense mutation in both families designated c.1091T→C (p.M364T). Haplotype analysis revealed that this is a founder mutation in the 3 families. Conclusion XLHED is a syndrome with variable clinical presentations that contain a spectrum of findings, including hypodontia. We suggest that XLRH should be grouped under XLHED as both share several phenotypic and genotypic similarities. PMID:20628232

  6. John D. Rockefeller 3rd, statesman and founder of the Population Council.

    PubMed

    Dunlop, J

    2000-01-01

    This article presents a profile of John D. Rockefeller 3rd, statesman and founder of the Population Council. It is noted that Rockefeller took a broad view of population control as a means to address poverty and economic development rather than as an end in itself. In 1952 he initiated the convocation of the Conference on Population Problems held in Williamsburg, Virginia. The discussion focused on food supply, industrial development, depletion of natural resources, and political instability resulting from unchecked population growth. In 1967, Rockefeller initiated, lobbied for, and finally achieved a World Leaders' Statement signed by 30 heads of state including US President Lyndon Johnson. The document drew attention to population growth as a world problem and engendered political support for family planning as a solution. After 3 years the Commission on Population Growth and the American Future was established, and Rockefeller was made its chairman. Several issues were debated, including more safer fertility control and the legalization of abortion. PMID:12349764

  7. Compositional assessments of key maize populations: B73 hybrids of the nested association mapping founder lines and diverse landrace inbred lines

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The present study provides an assessment of compositional diversity in maize B73 hybrids derived from both the nested association mapping (NAM) founder lines and from a geographically diverse collection of landrace accessions from North and South America. The NAM founders represent a key population...

  8. Characterization of an Italian Founder Mutation in the RING-Finger Domain of BRCA1

    PubMed Central

    Colombo, Mara; Congregati, Caterina; Sarkar, Mohosin; Magliery, Thomas J.; Ripamonti, Carla B.; Foglia, Claudia; Peissel, Bernard; Zaffaroni, Daniela; Manoukian, Siranoush; Tondini, Carlo; Barile, Monica; Pensotti, Valeria; Bernard, Loris

    2014-01-01

    The identification of founder mutations in cancer predisposing genes is important to improve risk assessment in geographically defined populations, since it may provide specific targets resulting in cost-effective genetic testing. Here, we report the characterization of the BRCA1 c.190T>C (p.Cys64Arg) mutation, mapped to the RING-finger domain coding region, that we detected in 43 hereditary breast/ovarian cancer (HBOC) families, for the large part originating from the province of Bergamo (Northern Italy). Haplotype analysis was performed in 21 families, and led to the identification of a shared haplotype extending over three BRCA1-associated marker loci (0.4 cM). Using the DMLE+2.2 software program and regional population demographic data, we were able to estimate the age of the mutation to vary between 3,100 and 3,350 years old. Functional characterization of the mutation was carried out at both transcript and protein level. Reverse transcriptase-PCR analysis on lymphoblastoid cells revealed expression of full length mRNA from the mutant allele. A green fluorescent protein (GFP)-fragment reassembly assay showed that the p.Cys64Arg substitution prevents the binding of the BRCA1 protein to the interacting protein BARD1, in a similar way as proven deleterious mutations in the RING-domain. Overall, 55 of 83 (66%) female mutation carriers had a diagnosis of breast and/or ovarian cancer. Our observations indicate that the BRCA1 c.190T>C is a pathogenic founder mutation present in the Italian population. Further analyses will evaluate whether screening for this mutation can be suggested as an effective strategy for the rapid identification of at-risk individuals in the Bergamo area. PMID:24516540

  9. Distribution and medical impact of loss-of-function variants in the Finnish founder population.

    PubMed

    Lim, Elaine T; Würtz, Peter; Havulinna, Aki S; Palta, Priit; Tukiainen, Taru; Rehnström, Karola; Esko, Tõnu; Mägi, Reedik; Inouye, Michael; Lappalainen, Tuuli; Chan, Yingleong; Salem, Rany M; Lek, Monkol; Flannick, Jason; Sim, Xueling; Manning, Alisa; Ladenvall, Claes; Bumpstead, Suzannah; Hämäläinen, Eija; Aalto, Kristiina; Maksimow, Mikael; Salmi, Marko; Blankenberg, Stefan; Ardissino, Diego; Shah, Svati; Horne, Benjamin; McPherson, Ruth; Hovingh, Gerald K; Reilly, Muredach P; Watkins, Hugh; Goel, Anuj; Farrall, Martin; Girelli, Domenico; Reiner, Alex P; Stitziel, Nathan O; Kathiresan, Sekar; Gabriel, Stacey; Barrett, Jeffrey C; Lehtimäki, Terho; Laakso, Markku; Groop, Leif; Kaprio, Jaakko; Perola, Markus; McCarthy, Mark I; Boehnke, Michael; Altshuler, David M; Lindgren, Cecilia M; Hirschhorn, Joel N; Metspalu, Andres; Freimer, Nelson B; Zeller, Tanja; Jalkanen, Sirpa; Koskinen, Seppo; Raitakari, Olli; Durbin, Richard; MacArthur, Daniel G; Salomaa, Veikko; Ripatti, Samuli; Daly, Mark J; Palotie, Aarno

    2014-07-01

    Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10⁻⁸) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10⁻¹¹⁷). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻⁴), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers. PMID

  10. Remembering Nancy. 25 Members of the Montessori Community Share Their Reflections on the Death of the AMS Founder.

    ERIC Educational Resources Information Center

    Turner, Joy; And Others

    1995-01-01

    Twenty-five members of the Montessori community share their memories of Dr. Nancy McCormick Rambusch, charismatic founder of the American Montessori movement, early childhood professional, and innovative educator, who died of pancreatic cancer on October 27, 1994. Rambusch's work of 40 years now flowers as an institutionalized educational program…

  11. Estimation of the number of founders of an invasive pest insect population: the fire ant Solenopsis invicta in the USA

    PubMed Central

    Ross, Kenneth G; Shoemaker, D. DeWayne

    2008-01-01

    Determination of the number of founders responsible for the establishment of invasive populations is important for developing biologically based management practices, predicting the invasive potential of species, and making inferences about ecological and evolutionary processes. The fire ant Solenopsis invicta is a major invasive pest insect first introduced into the USA from its native South American range in the mid-1930s. We use data from diverse genetic markers surveyed in the source population and the USA to estimate the number of founders of this introduced population. Data from different classes of nuclear markers (microsatellites, allozymes, sex-determination locus) and mitochondrial DNA are largely congruent in suggesting that 9–20 unrelated mated queens comprised the initial founder group to colonize the USA at Mobile, Alabama. Estimates of founder group size based on expanded samples from throughout the southern USA were marginally higher than this, consistent with the hypothesis of one or more secondary introductions of the ant into the USA. The rapid spread and massive population build-up of introduced S. invicta occurred despite the loss of substantial genetic variation associated with the relatively small invasive propagule size, a pattern especially surprising in light of the substantial genetic load imposed by the loss of variation at the sex-determination locus. PMID:18577505

  12. Apple founder targets healthcare as NeXT market. Interview by Carolyn Dunbar and Michael L. Laughlin.

    PubMed

    Jobs, S

    1992-12-01

    Cofounder and former chairman of the board of Apple Computer Steven Jobs looks beyond the 1980s image of a petulant, embittered young man, fighting with all who failed to share his vision, and many who did. Today, as a founder, president and chairman of NeXT, Inc., he looks to more high-minded applications of his computer genius. PMID:10122905

  13. TGfU--Would You Know It if You Saw It? Benchmarks from the Tacit Knowledge of the Founders

    ERIC Educational Resources Information Center

    Butler, Joy

    2014-01-01

    This paper explores the tacit expert knowledge and understanding about games curriculum and pedagogy of three men, Len Almond, David Bunker, and Rod Thorpe, credited as the founders of the Teaching Games for Understanding (TGfU) model. The model emerged from teacher practice in the late 1970s and was little theorized at the time, apart from a…

  14. The composition of the foundered complement to the continental crust and a re-evaluation of fluxes in arcs

    NASA Astrophysics Data System (ADS)

    Jagoutz, O.; Schmidt, M. W.

    2013-06-01

    Most primitive arc melts are basaltic in composition, yet the bulk continental crust, thought to be generated in arcs, is andesitic. In order to produce an andesitic crust from primitive arc basalts, rocks complementary to the andesitic crust have to be fractionated and subsequently removed, most likely through density sorting in the lower arc crust. The Kohistan Arc in northern Pakistan offers a unique opportunity to constrain the composition and volume of material fluxes involved in this process. In a lower crustal section >10 km cumulates (dunites, wehrlites, websterites, clinopyroxene-bearing garnetites and hornblendites, and garnet-gabbros) are exposed that are 0.1-0.3 g/cm3 denser than the underlying mantle. The cumulates combine with the andesitic bulk Kohistan Arc crust to reproduce the major and trace element composition of primitive basaltic arc melts. Our petrochemical analysis suggests that fractionation and subsequent foundering of wehrlites+ultramafic hornblende-garnet-clinopyroxene cumulates+garnet-gabbros is a viable mechanism for producing andesitic crust from a calc-alkaline/tholeiitic primitive high-Mg basalt. The mass of the foundered material is approximately twice that of the arc crust generated. For an overall andesitic arc composition, we estimate a magma flux into the arc (11-15 km3/yr) about three times the rate of arc crust production itself. Foundering fluxes of cumulates (6.4-8.1 km3/yr) are one third to half those of the globally subducted oceanic crust (~19 km3/yr). Hence, the delaminate forms a volumetrically significant, albeit refractory and depleted geochemical reservoir in the mantle. Owing to its low U/Pb and high Lu/Hf the foundered material evolves with time to a reservoir characterized by unradiogenic Pb and highly radiogenic Hf isotopes, unlike any of the common mantle endmembers defined by OIB chemistry. The unradiogenic Pb of the foundered arc cumulates could counterbalance the radiogenic Pb composition of the depleted

  15. [Emanuel Emeryk Machek (1852-1930)--founder of department of ophthalmology at the University of Lviv].

    PubMed

    Polak, Agnieszka; Grzybowski, Andrzej; Ręjdak, Robert

    2015-01-01

    In the 19th century, the process of social and political changes in the Polish society was considerably affected by the development of sciences, especially medicine. Many doctors were involved in voluntary health services and public education of the poorest social classes and in supporting government authorities which promoted health education and proper sanitation among the public. The article presents the intellectual biography of dr Emanuel Emeryk Machek, who was one of the most prominent doctors of that time, a competent clinician who trained many doctors and was engaged in voluntary work for the public. His medical career is connected with the history of Lviv University--Dr Emanuel Emeryk Machek was the founder of the Ophtalmic Hospital at the Medical Department of Lviv University. One of the students of dr Emanuel Emeryk Machek was dr Boleslaw Dlugoszowski, who is mostly remembered not as a doctor but as a great patriot, brave soldier fighting in the cavalry regiment, a friend and aide-de-camp of Marshall J6zef Pilsudski, a diplomat assigned by President Ignacy Moscicki to become his successor, and the President of Poland in October 1939. history of medicine, history of ophthalmology, Lviv University, history of Polish science under partitions, Boleslaw Wieniawa Dlugoszowski, Emanuel Emeryk Machek. PMID:26349161

  16. Identity-by-Descent-Based Phasing and Imputation in Founder Populations Using Graphical Models

    PubMed Central

    Palin, Kimmo; Campbell, Harry; Wright, Alan F; Wilson, James F; Durbin, Richard

    2011-01-01

    Accurate knowledge of haplotypes, the combination of alleles co-residing on a single copy of a chromosome, enables powerful gene mapping and sequence imputation methods. Since humans are diploid, haplotypes must be derived from genotypes by a phasing process. In this study, we present a new computational model for haplotype phasing based on pairwise sharing of haplotypes inferred to be Identical-By-Descent (IBD). We apply the Bayesian network based model in a new phasing algorithm, called systematic long-range phasing (SLRP), that can capitalize on the close genetic relationships in isolated founder populations, and show with simulated and real genome-wide genotype data that SLRP substantially reduces the rate of phasing errors compared to previous phasing algorithms. Furthermore, the method accurately identifies regions of IBD, enabling linkage-like studies without pedigrees, and can be used to impute most genotypes with very low error rate. Genet. Epidemiol. 2011. © 2011 Wiley Periodicals, Inc.35:853-860, 2011 PMID:22006673

  17. Characterization of a novel founder MSH6 mutation causing Lynch syndrome in the French Canadian population.

    PubMed

    Castellsagué, E; Liu, J; Volenik, A; Giroux, S; Gagné, R; Maranda, B; Roussel-Jobin, A; Latreille, J; Laframboise, R; Palma, L; Kasprzak, L; Marcus, V A; Breguet, M; Nolet, S; El-Haffaf, Z; Australie, K; Gologan, A; Aleynikova, O; Oros-Klein, K; Greenwood, C; Mes-Masson, A M; Provencher, D; Tischkowitz, M; Chong, G; Rousseau, F; Foulkes, W D

    2015-06-01

    We identified an MSH6 mutation (c.10C>T, p.Gln4*) causing Lynch syndrome (LS) in 11 French Canadian (FC) families from the Canadian province of Quebec. We aimed to investigate the molecular and clinical implications of this mutation among FC carriers and to assess its putative founder origin. We studied 11 probands and 27 family members. Additionally 6433 newborns, 187 colorectal cancer (CRC) cases, 381 endometrial cancer (EC) cases and 179 additional controls, all of them from Quebec, were used. Found in approximately 1 of 400 newborns, the mutation is one of the most common LS mutations described. We have found that this mutation confers a greater risk for EC than for CRC, both in the 11 studied families and in the unselected cases: EC [odds ratio (OR) = 7.5, p < 0.0001] and CRC (OR = 2.2, p = 0.46). Haplotype analyses showed that the mutation arose in a common ancestor, probably around 430-656 years ago, coinciding with the arrival of the first French settlers. Application of the results of this study could significantly improve the molecular testing and clinical management of LS families in Quebec. PMID:25318681

  18. Auxin-regulated chromatin switch directs acquisition of flower primordium founder fate

    PubMed Central

    Wu, Miin-Feng; Yamaguchi, Nobutoshi; Xiao, Jun; Bargmann, Bastiaan; Estelle, Mark; Sang, Yi; Wagner, Doris

    2015-01-01

    Reprogramming of cell identities during development frequently requires changes in the chromatin state that need to be restricted to the correct cell populations. Here we identify an auxin hormone-regulated chromatin state switch that directs reprogramming from transit amplifying to primordium founder cell fate in Arabidopsis inflorescences. Upon auxin sensing, the MONOPTEROS transcription factor recruits SWI/SNF chromatin remodeling ATPases to increase accessibility of the DNA for induction of key regulators of flower primordium initiation. In the absence of the hormonal cue, auxin sensitive Aux/IAA proteins bound to MONOPTEROS block recruitment of the SWI/SNF chromatin remodeling ATPases in addition to recruiting a co-repressor/histone deacetylase complex. This simple and elegant hormone-mediated chromatin state switch is ideally suited for iterative flower primordium initiation and orchestrates additional auxin-regulated cell fate transitions. Our findings establish a new paradigm for nuclear response to auxin. They also provide an explanation for how this small molecule can direct diverse plant responses. DOI: http://dx.doi.org/10.7554/eLife.09269.001 PMID:26460543

  19. Chronic intestinal pseudo-obstruction in a child harboring a founder Hirschsprung RET mutation.

    PubMed

    Rossi, Valentina; Mosconi, Manuela; Nozza, Paolo; Murgia, Daniele; Mattioli, Girolamo; Ceccherini, Isabella; Pini Prato, Alessio

    2016-09-01

    Chronic intestinal pseudo obstruction (CIPO) is a rare clinical entity characterized by symptoms and signs of intestinal obstruction without either recognizable anatomical abnormalities or intestinal aganglionosis. A Chinese female infant presented to our institution with a clinical diagnosis of CIPO. Aganglionosis was ruled out by full thickness colonic and ileal biopsies and by rectal suction biopsies. Unexpectedly, direct sequencing and PCR amplification of RET proto-oncogene from peripheral blood extracted DNA identified a RET R114H mutation. This mutation has already been reported as strongly associated with Asian patients affected by Hirschsprung's disease (HSCR) and is considered a founder mutation in Asia. The same mutation has never been reported in patients with CIPO, so far. These findings support the role of RET in the development of the enteric nervous system but underline the importance of other genetic or environmental factors contributing to the gastrointestinal phenotype of the disease. Somehow, this RET R114H mutation proved to have a role in the etiology of both CIPO and HSCR and could contribute to a more diffuse imbalance of gut dysmotility. © 2016 Wiley Periodicals, Inc. PMID:27273837

  20. Founder Fukutin mutation causes Walker-Warburg syndrome in four Ashkenazi Jewish families†

    PubMed Central

    Chang, Wendy; Winder, Thomas L.; LeDuc, Charles A.; Simpson, Lynn L.; Millar, William S.; Dungan, Jeffrey; Ginsberg, Norman; Plaga, Stacey; Moore, Steven A.; Chung, Wendy K.

    2009-01-01

    Objective Walker-Warburg syndrome (WWS) is a genetically heterogeneous congenital muscular dystrophy caused by abnormal glycosylation of α-dystroglycan (α-DG) that is associated with brain malformations and eye anomalies. The Fukutin (FKTN) gene, which causes autosomal recessively inherited WWS is most often associated with Fukuyama congenital muscular dystrophy in Japan. We describe the clinical features of four nonconsanguinous Ashkenazi Jewish families with WWS and identify the underlying genetic basis for WWS. Method We screened for mutations in POMGnT1, POMT1, POMT2, and FKTN, genes causing WWS, by dideoxy sequence analysis. Results We identified an identical homozygous c.1167insA mutation in the FKTN gene on a common haplotype in all four families and identified 2/299 (0.7%) carriers for the c.1167insA mutation among normal American Ashkenazi Jewish adults. Conclusion These data suggest that the c.1167insA FKTN mutation described by us is a founder mutation that can be used to target diagnostic testing and carrier screening in the Ashkenazi Jewish population. PMID:19266496

  1. Auxin-regulated chromatin switch directs acquisition of flower primordium founder fate.

    PubMed

    Wu, Miin-Feng; Yamaguchi, Nobutoshi; Xiao, Jun; Bargmann, Bastiaan; Estelle, Mark; Sang, Yi; Wagner, Doris

    2015-01-01

    Reprogramming of cell identities during development frequently requires changes in the chromatin state that need to be restricted to the correct cell populations. Here we identify an auxin hormone-regulated chromatin state switch that directs reprogramming from transit amplifying to primordium founder cell fate in Arabidopsis inflorescences. Upon auxin sensing, the MONOPTEROS transcription factor recruits SWI/SNF chromatin remodeling ATPases to increase accessibility of the DNA for induction of key regulators of flower primordium initiation. In the absence of the hormonal cue, auxin sensitive Aux/IAA proteins bound to MONOPTEROS block recruitment of the SWI/SNF chromatin remodeling ATPases in addition to recruiting a co-repressor/histone deacetylase complex. This simple and elegant hormone-mediated chromatin state switch is ideally suited for iterative flower primordium initiation and orchestrates additional auxin-regulated cell fate transitions. Our findings establish a new paradigm for nuclear response to auxin. They also provide an explanation for how this small molecule can direct diverse plant responses. PMID:26460543

  2. Metachronous pancreatic cancer originating from disseminated founder pancreatic intraductal neoplasias (PanINs).

    PubMed

    Imai, Koji; Karasaki, Hidenori; Ono, Yusuke; Sasajima, Junpei; Chiba, Shin-Ichi; Funakoshi, Hiroshi; Muraki, Miho; Hanaoka, Hideki; Furukawa, Takahisa; Furukawa, Hiroyuki; Kono, Toru; Nagashima, Kazuo; Mizukami, Yusuke

    2015-04-01

    Clonal populations originated from benign-looking 'founder cells' may spread widely within pancreas instead of being localized in situ before frank pancreatic ductal adenocarcinoma (PDA) can be detected. Metachronous PDA is not common event, and we here sought to define potent origin of multiple PDAs developed in a woman using advanced genetics technologies. Curative resection of pancreatic head tumour was performed; however, 'recurrent' lesions in the remnant pancreas were found 3.5 years later and total pancreatectomy was subsequently performed. The metachronous lesions were morphologically similar to the primary PDA. Using a next-generation sequencing and digital PCR, all three PDAs were shown to possess rare somatic mutations in KRAS (p.T58I & p.Q61H). Curiously, identical KRAS mutations were found in low-grade 'intraepithelial' lesions, which localized in normal area of the pancreas and one of them possessed p53 mutation, which was also found in the PDAs. The footprint of the tumour evolution marked by mutational profiling supports a human correlate to the mouse models of 'dissemination' occurring at the earliest stages of pancreatic neoplasia. PMID:27499895

  3. Metachronous pancreatic cancer originating from disseminated founder pancreatic intraductal neoplasias (PanINs)

    PubMed Central

    Imai, Koji; Karasaki, Hidenori; Ono, Yusuke; Sasajima, Junpei; Chiba, Shin‐ichi; Funakoshi, Hiroshi; Muraki, Miho; Hanaoka, Hideki; Furukawa, Takahisa; Furukawa, Hiroyuki; Kono, Toru; Nagashima, Kazuo

    2015-01-01

    Abstract Clonal populations originated from benign‐looking ‘founder cells' may spread widely within pancreas instead of being localized in situ before frank pancreatic ductal adenocarcinoma (PDA) can be detected. Metachronous PDA is not common event, and we here sought to define potent origin of multiple PDAs developed in a woman using advanced genetics technologies. Curative resection of pancreatic head tumour was performed; however, ‘recurrent' lesions in the remnant pancreas were found 3.5 years later and total pancreatectomy was subsequently performed. The metachronous lesions were morphologically similar to the primary PDA. Using a next‐generation sequencing and digital PCR, all three PDAs were shown to possess rare somatic mutations in KRAS (p.T58I & p.Q61H). Curiously, identical KRAS mutations were found in low‐grade ‘intraepithelial' lesions, which localized in normal area of the pancreas and one of them possessed p53 mutation, which was also found in the PDAs. The footprint of the tumour evolution marked by mutational profiling supports a human correlate to the mouse models of ‘dissemination' occurring at the earliest stages of pancreatic neoplasia.

  4. Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence.

    PubMed

    Tan-Sindhunata, M Brigita; Mathijssen, Inge B; Smit, Margriet; Baas, Frank; de Vries, Johanna I; van der Voorn, J Patrick; Kluijt, Irma; Hagen, Marleen A; Blom, Eveline W; Sistermans, Erik; Meijers-Heijboer, Hanne; Waisfisz, Quinten; Weiss, Marjan M; Groffen, Alexander J

    2015-09-01

    Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing. PMID:25537362

  5. Are continental “adakites” derived from thickened or foundered lower crust?

    NASA Astrophysics Data System (ADS)

    Ma, Qiang; Zheng, Jian-Ping; Xu, Yi-Gang; Griffin, William L.; Zhang, Rui-Sheng

    2015-06-01

    The geochemical signatures of "adakites" are usually attributed to high-pressure (≥ 50 km) partial melting of mafic rocks, and accordingly the occurrence of adakitic magmas in continental settings is frequently used as an indicator of a thickened or foundered lower crust at the time of magma emplacement. These premises are built on experiments and modeling using an MORB-like source, but the probable source of continental "adakites" (i.e., continental lower crust) is compositionally different from MORB. To elucidate the effect of source inheritance and pressure on resultant melts, geochemical analyses and trace-element modeling have been carried out on Jurassic adakitic rocks from the northern part of the North China Craton. The results show that these continental adakitic melts can be generated at depths less than 40 km, and their "adakitic" signature is most likely inherited from their source rocks. Such conclusions can be applied to the Mesozoic adakitic magmas from the interior of the North China Craton. Only the "adakites" from collisional orogens (i.e., Tibet, Dabie UHP belt) require crustal melting at depths greater than 50 km, consistent with collision-induced crustal thickening in these areas. This study therefore highlights the importance of source composition when defining the formation conditions of magmatic rocks in general, and in particular questions the common use of "adakites" as an indicator of specific geodynamic situations.

  6. Founders, Drift, and Infidelity: The Relationship between Y Chromosome Diversity and Patrilineal Surnames

    PubMed Central

    King, Turi E.

    2009-01-01

    Most heritable surnames, like Y chromosomes, are passed from father to son. These unique cultural markers of coancestry might therefore have a genetic correlate in shared Y chromosome types among men sharing surnames, although the link could be affected by mutation, multiple foundation for names, nonpaternity, and genetic drift. Here, we demonstrate through an analysis of 1,678 Y-chromosomal haplotypes within 40 British surnames a remarkably high degree of coancestry that generally increases as surnames become rarer. On average, the proportion of haplotypes lying within descent clusters is 62% but ranges from 0% to 87%. The shallow time depth of many descent clusters within names, the lack of a detectable effect of surname derivation on diversity, and simulations of surname descent suggest that genetic drift through variation in reproductive success is important in structuring haplotype diversity. Modern patterns therefore provide little reliable information about the original founders of surnames some 700 years ago. A comparative analysis of published data on Y diversity within Irish surnames demonstrates a relative lack of surname frequency dependence of coancestry, a difference probably mediated through distinct Irish and British demographic histories including even more marked genetic drift in Ireland. PMID:19204044

  7. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus

    PubMed Central

    Liao, Hua-Xin; Lynch, Rebecca; Zhou, Tongqing; Gao, Feng; Alam, S. Munir; Boyd, Scott D.; Fire, Andrew Z.; Roskin, Krishna M.; Schramm, Chaim A.; Zhang, Zhenhai; Zhu, Jiang; Shapiro, Lawrence; Mullikin, James C.; Gnanakaran, S.; Hraber, Peter; Wiehe, Kevin; Kelsoe, Garnett; Yang, Guang; Xia, Shi-Mao; Montefiori, David C.; Parks, Robert; Lloyd, Krissey E.; Scearce, Richard M.; Soderberg, Kelly A.; Cohen, Myron; Kaminga, Gift; Louder, Mark K.; Tran, Lillan M.; Chen, Yue; Cai, Fangping; Chen, Sheri; Moquin, Stephanie; Du, Xiulian; Joyce, Gordon M.; Srivatsan, Sanjay; Zhang, Baoshan; Zheng, Anqi; Shaw, George M.; Hahn, Beatrice H.; Kepler, Thomas B.; Korber, Bette T.M.; Kwong, Peter D.; Mascola, John R.; Haynes, Barton F.

    2013-01-01

    Current HIV-1 vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in ~20% of HIV-1-infected individuals, and details of their generation could provide a roadmap for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from time of infection. The mature antibody, CH103, neutralized ~55% of HIV-1 isolates, and its co-crystal structure with gp120 revealed a novel loop-based mechanism of CD4-binding site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the CH103-lineage unmutated common ancestor avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data elucidate the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies and provide insights into strategies to elicit similar antibodies via vaccination. PMID:23552890

  8. Willet M. Hays, great benefactor to plant breeding and the founder of our association.

    PubMed

    Troyer, A F; Stoehr, H

    2003-01-01

    Willet M. Hays was a great benefactor to plant breeding and the founder of the American Genetic Association (AGA). We commemorate the AGA's centennial. We mined university archives, U.S. Department of Agriculture (USDA) yearbooks, plant breeding textbooks, scientific periodicals, and descendants for information. Willet Hays first recognized the individual plant as the unit of selection and started systematic pure-line selection and progeny tests in 1888. He developed useful plant breeding methods. He selected superior flax (Linum usitatissimum L.), wheat (Triticum vulgare L.), corn (Zea mays L.), barley (Hordeum vulgare L.), and oat (Avena sativa L.) varieties, and discovered Grimm alfalfa (Medicago sativa L.); all became commercially important. He initiated branch stations for better performance testing. Willet Hays befriended colleagues in other universities, in federal stations, in a London conference, and in Europe. He gathered and spread the scientific plant breeding gospel. He also improved rural roads and initiated animal breeding records and agricultural economics records. He started the AGA in 1903, serving as secretary for 10 years. He became assistant secretary of agriculture in 1904. He introduced the project system for agricultural research. He authored or coauthored the Nelson Amendment, the Smith-Lever Act, the Smith-Hughes Act, and the protocol leading to the United Nations Food and Agriculture Organization-all involved teaching agricultural practices that improved the world. PMID:14691309

  9. Animal personality meets community ecology: founder species aggression and the dynamics of spider communities.

    PubMed

    Quinn, John L

    2015-11-01

    Silken web-reef created by the spider Anelosimus studiosus (main picture) and close-up (insert picture) of multi-female, adult colony of the same species. (photographs: T. Jones, J. Pruitt and A. Wild) In Focus: Pruitt, J.N. & Modlmeier, A.P. (2015) Animal personality in a foundation species drives community divergence and collapse in the wild. Journal of Animal Ecology, 84 Interspecific interactions form the cornerstone of niche theory in community ecology. The 7-year study In Focus here supports the view that variation within species could also be crucially important. Spider communities created experimentally in the wild, with either aggressive or docile individuals of the same founder species, were highly divergent in patterns of community succession for several years. Eventually, they converged on the same community composition only to collapse entirely shortly after, apparently because of the specific mix of aggression phenotypes within and between species just before collapse. These results suggest numerous avenues of research for behavioural ecology and evolutionary community ecology in metapopulations, and could help to resolve differences between competing theories. PMID:26449191

  10. Mitochondrial DNA Analysis of Mongolian Populations and Implications for the Origin of New World Founders

    PubMed Central

    Kolman, C. J.; Sambuughin, N.; Bermingham, E.

    1996-01-01

    High levels of mitochondrial DNA (mtDNA) diversity were determined for Mongolian populations, represented by the Mongol-speaking Khalkha and Dariganga. Although 103 samples were collected across Mongolia, low levels of genetic substructuring were detected, reflecting the nomadic lifestyle and relatively recent ethnic differentiation of Mongolian populations. mtDNA control region I sequence and seven additional mtDNA polymorphisms were assayed to allow extensive comparison with previous human population studies. Based on a comparative analysis, we propose that indigenous populations in east Central Asia represent the closest genetic link between Old and New World populations. Utilizing restriction/deletion polymorphisms, Mongolian populations were found to carry all four New World founding haplogroups as defined by WALLACE and coworkers. The ubiquitous presence of the four New World haplogroups in the Americas but narrow distribution across Asia weakens support for GREENBERG and coworkers' theory of New World colonization via three independent migrations. The statistical and geographic scarcity of New World haplogroups in Asia makes it improbable that the same four haplotypes would be drawn from one geographic region three independent times. Instead, it is likely that founder effects manifest throughout Asia and the Americas are responsible for differences in mtDNA haplotype frequencies observed in these regions. PMID:8846908

  11. Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence

    PubMed Central

    Tan-Sindhunata, M Brigita; Mathijssen, Inge B; Smit, Margriet; Baas, Frank; de Vries, Johanna I; van der Voorn, J Patrick; Kluijt, Irma; Hagen, Marleen A; Blom, Eveline W; Sistermans, Erik; Meijers-Heijboer, Hanne; Waisfisz, Quinten; Weiss, Marjan M; Groffen, Alexander J

    2015-01-01

    Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing. PMID:25537362

  12. Shipwrecks and founder effects: divergent demographic histories reflected in Caribbean mtDNA.

    PubMed

    Salas, Antonio; Richards, Martin; Lareu, María-Victoria; Sobrino, Beatriz; Silva, Sandra; Matamoros, Mireya; Macaulay, Vincent; Carracedo, Angel

    2005-12-01

    During the period of the Atlantic slave trade (15th-19th centuries), millions of people were forced to move from Africa to many American destinations, changing dramatically the human landscape of the Americas. Here, we analyze mitochondrial DNA from two different American populations with African ancestry, with hitherto unknown European and Native American components. On the basis of historical records, African-Americans from Chocó (Colombia) and the Garífunas (or "Black Carib") of Honduras are likely to have had very different demographic histories, with a significant founder effect in the formation of the latter. Both the common features and differences are reflected in their mtDNA composition. Both show a minor component (approximately 16%) from Native Central/South Americans and a larger component (approximately 84%) from sub-Saharan Africans. The latter component is very diverse in the African-Americans from Chocó, similar to that of sub-Saharan Africans, but much less so in the Garífunas, with several mtDNA types elevated to high frequency, suggesting the action of genetic drift. PMID:16047324

  13. [Dr. Lazar Nenadović, gynecologist-obstetrician and founder of balneology and physical medicine in Serbia].

    PubMed

    Berić, B; Dokmanović-Dordević, M

    1990-01-01

    Prof. Dr. Lazar-Laza Nenadović specialist in obstetrics and gynaecology (Modos, 1870--Beograd, 1939), the founder of advanced physical medicine and balneo-climatology in Serbia. Prof. Nenadović, besides a series of papers on obstetrics and gynaecology, is the author of a monograph on obstetrics and gynaecology published in Novi Sad in 1912, being the first of this kind in Serbia. Its title is Diseases of the female, their origin, causes and treatment. He was also one of the pioneers of gynecologic balneology in Yugoslavia and one of the founders of the Belgrade School of Obstetrics and Gynaecology, as well as a close collaborator and friend of Prof. Dr Milos Bogdanović, the first head and professor of the Department of Obstetrics and Gynaecology of the School of Medicine in Belgrade. PMID:2214860

  14. Linkage disequilibrium analysis in young populations: pseudo-vitamin D-deficiency rickets and the founder effect in French Canadians.

    PubMed

    Labuda, M; Labuda, D; Korab-Laskowska, M; Cole, D E; Zietkiewicz, E; Weissenbach, J; Popowska, E; Pronicka, E; Root, A W; Glorieux, F H

    1996-09-01

    Pseudo-vitamin D-deficiency rickets (PDDR) was mapped close to D12S90 and between proximal D12S312 and distal (D12S305, D12S104) microsatellites that were subsequently found on a single YAC clone. Analysis of a complex haplotype in linkage disequilibrium (LD) with the disease discriminated among distinct founder effects in French Canadian populations in Acadia and in Charlevoix-Saguenay-Lac-Saint-Jean (Ch-SLSJ), as well as an earlier one in precolonial Europe. A simple demographic model suggested the historical age of the founder effect in Ch-SLSJ to be approximately 12 generations. The corresponding LD data are consistent with this figure when they are analyzed within the framework of Luria-Delbrück model, which takes into account the population growth. Population sampling due to a limited number of first settlers and the rapid demographic expansion appear to have played a major role in the founding of PDDR in Ch-SLSJ and, presumably, other genetic disorders endemic to French Canada. Similarly, the founder effect in Ashkenazim, coinciding with their early settlement in medieval Poland and subsequent expansion eastward, could explain the origin of frequent genetic diseases in this population. PMID:8751865

  15. Investigations of the Y Chromosome, Male Founder Structure and YSTR Mutation Rates in the Old Order Amish

    PubMed Central

    Pollin, Toni I.; McBride, Daniel J.; Agarwala, Richa; Schäffer, Alejandro A.; Shuldiner, Alan R.; Mitchell, Braxton D.; O'Connell, Jeffrey R.

    2007-01-01

    Objectives Using Y chromosome short tandem repeat (YSTR) genotypes, (1) evaluate the accuracy and completeness of the Lancaster County Old Order Amish (OOA) genealogical records and (2) estimate YSTR mutation rates. Methods Nine YSTR markers were genotyped in 739 Old Order Amish males who participated in several ongoing genetic studies of complex traits and could be connected into one of 28 all-male lineage pedigrees constructed using the Anabaptist Genealogy Database and the query software PedHunter. A putative founder YSTR haplotype was constructed for each pedigree, and observed and inferred father-son transmissions were used to estimate YSTR mutation rates. Results We inferred 27 distinct founder Y chromosome haplotypes in the 28 male lineages, which encompassed 27 surnames accounting for 98% of Lancaster OOA households. Nearly all deviations from founder haplotypes were consistent with mutation events rather than errors. The estimated marker-specific mutation rates ranged from 0 to 1.09% (average 0.33% using up to 283 observed meioses only and 0.28% using up to 1,232 observed and inferred meioses combined). Conclusions These data confirm the accuracy and completeness of the male lineage portion of the Anabaptist Genealogy Database and contribute mutation rate estimates for several commonly used Y chromosome STR markers. PMID:17898540

  16. Identification of full-length transmitted/founder viruses and their progeny in primary HIV-1 infection

    SciTech Connect

    Korber, Bette; Hraber, Peter; Giorgi, Elena; Bhattacharya, T

    2009-01-01

    Identification of transmitted/founder virus genomes and their progeny by is a novel strategy for probing the molecular basis of HIV-1 transmission and for evaluating the genetic imprint of viral and host factors that act to constrain or facilitate virus replication. Here, we show in a cohort of twelve acutely infected subjects (9 clade B; 3 clade C), that complete genomic sequences of transmitted/founder viruses could be inferred using single genome amplification of plasma viral RNA, direct amplicon sequencing, and a model of random virus evolution. This allowed for the precise identification, chemical synthesis, molecular cloning, and biological analysis of those viruses actually responsible for productive clinical infection and for a comprehensive mapping of sequential viral genomes and proteomes for mutations that are necessary or incidental to the establishment of HIV-1 persistence. Transmitted/founder viruses were CD4 and CCR5 tropic, replicated preferentially in activated primary T-Iymphocytes but not monocyte-derived macrophages, and were effectively shielded from most heterologous or broadly neutralizing antibodies. By 3 months of infection, the evolving viral quasispecies in three subjects showed mutational fixation at only 2-5 discreet genomic loci. By 6-12 months, mutational fixation was evident at 18-27 genomic loci. Some, but not all, of these mutations were attributable to virus escape from cytotoxic Tlymphocytes or neutralizing antibodies, suggesting that other viral or host factors may influence early HIV -1 fitness.

  17. Diversification in the tropical pacific: comparisons between marine and terrestrial systems and the importance of founder speciation.

    PubMed

    Paulay, Gustav; Meyer, Chris

    2002-11-01

    Patterns of distribution and processes of differentiation have often been contrasted between terrestrial and marine biotas. The islands of Oceania offer an excellent setting to explore this contrast, because the geographic setting for terrestrial and shallow-water, benthic, marine organisms are the same: the myriad islands strewn across the vast Pacific. The size of species ranges and the geographic distribution of endemism are two biogeographic attributes that are thought to differ markedly between terrestrial and marine biotas in the Pacific. While terrestrial species are frequently confined to single islands or archipelagoes throughout Oceania, marine species tend to have wide to very wide distributions, and are rarely restricted to single island groups except for the most isolated archipelagoes. We explore the conditions under which species can reach an island by dispersal and differentiate. Genetic differentiation can occur either through founder speciation or vicariance; these processes are requisite ends of a continuum. We show that founder speciation is most likely when few propagules enter the dispersal medium and survive well while they travel far. We argue that conditions favorable to founder speciation are common in marine as well as terrestrial systems, and that terrestrial-type, archipelagic-level endemism is likely common in marine taxa. We give examples of marine groups that show archipelagic level endemism on most Pacific island groups as well as of terrestrial species that are widespread. Thus both the patterns and processes of insular diversification are variable, and overlap more between land and sea than previously considered. PMID:21680372

  18. Estimation of the number of founders of an invasive pest insect population: the fire ant Solenopsis incivta in the United States

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Determination of the number of founders responsible for the establishment of invasive plant and animal populations is important for developing biologically based management practices, predicting the invasive potential of species, and making inferences about basic ecological and evolutionary processe...

  19. Testing founder effect speciation: Divergence population genetics of the Spoonbills Platalea regia and Pl. minor (Threskiornithidae, Aves)

    USGS Publications Warehouse

    Yeung, Carol K.L.; Tsai, Pi-Wen; Chesser, R. Terry; Lin, Rong-Chien; Yao, Cheng-Te; Tian, Xiu-Hua; Li, Shou-Hsien

    2011-01-01

    Although founder effect speciation has been a popular theoretical model for the speciation of geographically isolated taxa, its empirical importance has remained difficult to evaluate due to the intractability of past demography, which in a founder effect speciation scenario would involve a speciational bottleneck in the emergent species and the complete cessation of gene flow following divergence. Using regression-weighted approximate Bayesian computation, we tested the validity of these two fundamental conditions of founder effect speciation in a pair of sister species with disjunct distributions: the royal spoonbill Platalea regia in Australasia and the black-faced spoonbill Pl. minor in eastern Asia. When compared with genetic polymorphism observed at 20 nuclear loci in the two species, simulations showed that the founder effect speciation model had an extremely low posterior probability (1.55 × 10-8) of producing the extant genetic pattern. In contrast, speciation models that allowed for postdivergence gene flow were much more probable (posterior probabilities were 0.37 and 0.50 for the bottleneck with gene flow and the gene flow models, respectively) and postdivergence gene flow persisted for a considerable period of time (more than 80% of the divergence history in both models) following initial divergence (median = 197,000 generations, 95% credible interval [CI]: 50,000-478,000, for the bottleneck with gene flow model; and 186,000 generations, 95% CI: 45,000-477,000, for the gene flow model). Furthermore, the estimated population size reduction in Pl. regia to 7,000 individuals (median, 95% CI: 487-12,000, according to the bottleneck with gene flow model) was unlikely to have been severe enough to be considered a bottleneck. Therefore, these results do not support founder effect speciation in Pl. regia but indicate instead that the divergence between Pl. regia and Pl. minor was probably driven by selection despite continuous gene flow. In this light, we

  20. A founder mutation in Anoctamin 5 is a major cause of limb girdle muscular dystrophy

    PubMed Central

    Muelas, Nuria; Köehler, Katrin; Huebner, Angela; Hudson, Gavin; Chinnery, Patrick F.; Barresi, Rita; Eagle, Michelle; Polvikoski, Tuomo; Bailey, Geraldine; Miller, James; Radunovic, Aleksander; Hughes, Paul J.; Roberts, Richard; Krause, Sabine; Walter, Maggie C.; Laval, Steven H.; Straub, Volker; Lochmüller, Hanns; Bushby, Kate

    2014-01-01

    The limb girdle muscular dystrophies (LGMDs) are a group of disorders with wide genetic and clinical heterogeneity. Recently, mutations in the ANO5 gene, which encodes a putative calcium-activated chloride channel belonging to the Anoctamin family of proteins, were identified in five families with one of two previously identified disorders, LGMD2L and non-dysferlin Miyoshi muscular dystrophy (MMD3). We screened a candidate group of 64 patients from 59 British and German kindreds and found the truncating mutation, c.191dupA in exon 5 of ANO5 in 20 patients, homozygously in 15 and in compound heterozygosity with other ANO5 variants in the rest. An intragenic SNP and an extragenic microsatellite marker are in linkage disequilibrium with the mutation, suggesting a founder effect in the Northern European population. We have further defined the clinical phenotype of ANO5-associated muscular dystrophy. Patients show adult onset proximal lower limb weakness with highly raised creatinine kinase (CK) values (average 4500 IU/l) and frequent muscle atrophy and asymmetry of muscle involvement. Onset varies from the early 20s to 50s and the weakness is generally slowly progressive, with most patients remaining ambulant for several decades. Distal presentation is much less common but a milder degree of distal lower limb weakness is often observed. Upper limb strength is only mildly affected and cardiac and respiratory function is normal. Females appear less frequently affected. In the North of England population we have identified eight patients with ANO5 mutations, suggesting a minimum prevalence of 0.27/100 000, twice as common as dysferlinopathy. We suggest that mutations in ANO5 represent a relatively common cause of adult onset muscular dystrophy with high CK and that mutation screening, particularly of the common mutation c.191dupA, should be an early step in the diagnostic algorithm of adult LGMD patients. PMID:21186264

  1. Susceptibility to quantum dot induced lung inflammation differs widely among the Collaborative Cross founder mouse strains.

    PubMed

    Scoville, David K; White, Collin C; Botta, Dianne; McConnachie, Lisa A; Zadworny, Megan E; Schmuck, Stefanie C; Hu, Xiaoge; Gao, Xiaohu; Yu, Jianbo; Dills, Russell L; Sheppard, Lianne; Delaney, Martha A; Griffith, William C; Beyer, Richard P; Zangar, Richard C; Pounds, Joel G; Faustman, Elaine M; Kavanagh, Terrance J

    2015-12-01

    Quantum dots (QDs) are engineered semiconductor nanoparticles with unique physicochemical properties that make them potentially useful in clinical, research and industrial settings. However, a growing body of evidence indicates that like other engineered nanomaterials, QDs have the potential to be respiratory hazards, especially in the context of the manufacture of QDs and products containing them, as well as exposures to consumers using these products. The overall goal of this study was to investigate the role of mouse strain in determining susceptibility to QD-induced pulmonary inflammation and toxicity. Male mice from 8 genetically diverse inbred strains (the Collaborative Cross founder strains) were exposed to CdSe-ZnS core-shell QDs stabilized with an amphiphilic polymer. QD treatment resulted in significant increases in the percentage of neutrophils and levels of cytokines present in bronchoalveolar lavage fluid (BALF) obtained from NOD/ShiLtJ and NZO/HlLtJ mice relative to their saline (Sal) treated controls. Cadmium measurements in lung tissue indicated strain-dependent differences in disposition of QDs in the lung. Total glutathione levels in lung tissue were significantly correlated with percent neutrophils in BALF as well as with lung tissue Cd levels. Our findings indicate that QD-induced acute lung inflammation is mouse strain dependent, that it is heritable, and that the choice of mouse strain is an important consideration in planning QD toxicity studies. These data also suggest that formal genetic analyses using additional strains or recombinant inbred strains from these mice could be useful for discovering potential QD-induced inflammation susceptibility loci. PMID:26476918

  2. Identification of a founder mutation in TPM3 in nemaline myopathy patients of Turkish origin.

    PubMed

    Lehtokari, Vilma-Lotta; Pelin, Katarina; Donner, Kati; Voit, Thomas; Rudnik-Schöneborn, Sabine; Stoetter, Mechthild; Talim, Beril; Topaloglu, Haluk; Laing, Nigel G; Wallgren-Pettersson, Carina

    2008-09-01

    To date, six genes are known to cause nemaline (rod) myopathy (NM), a rare congenital neuromuscular disorder. In an attempt to find a seventh gene, we performed linkage and subsequent sequence analyses in 12 Turkish families with recessive NM. We found homozygosity in two of the families at 1q12-21.2, a region encompassing the gamma-tropomyosin gene (TPM3) encoding slow skeletal muscle alpha-tropomyosin, a known NM gene. Sequencing revealed homozygous deletion of the first nucleotide of the last exon, c.913delA of TPM3 in both families. The mutation removes the last nucleotide before the stop codon, causing a frameshift and readthrough across the termination signal. The encoded alphaTm(slow) protein is predicted to be 73 amino acids longer than normal, and the extension to the protein is hypothesised to be unable to form a coiled coil. The resulting tropomyosin protein may therefore be non-functional. The affected children in both families were homozygous for the mutation, while the healthy parents were mutation carriers. Both of the patients in Family 1 had the severe form of NM, and also an unusual chest deformity. The affected children in Family 2 had the intermediate form of NM. Muscle biopsies showed type 1 (slow) fibres to be markedly smaller than type 2 (fast) fibres. Previously, there had been five reports, only, of NM caused by mutations in TPM3. The mutation reported here is the first deletion to be identified in TPM3, and it is likely to be a founder mutation in the Turkish population. PMID:18382475

  3. Tissue-specific responses to the LRPPRC founder mutation in French Canadian Leigh Syndrome

    PubMed Central

    Sasarman, Florin; Nishimura, Tamiko; Antonicka, Hana; Weraarpachai, Woranontee; Shoubridge, Eric A.; Allen, Bruce; Burelle, Yan; Charron, Guy; Coderre, Lise; DesRosiers, Christine; Laprise, Catherine; Morin, Charles; Rioux, John; Shoubridge, Eric A.

    2015-01-01

    French Canadian Leigh Syndrome (LSFC) is an early-onset, progressive neurodegenerative disorder with a distinct pattern of tissue involvement. Most cases are caused by a founder missense mutation in LRPPRC. LRPPRC forms a ribonucleoprotein complex with SLIRP, another RNA-binding protein, and this stabilizes polyadenylated mitochondrial mRNAs. LSFC fibroblasts have reduced levels of LRPPRC and a specific complex IV assembly defect; however, further depletion of mutant LRPPRC results in a complete failure to assemble a functional oxidative phosphorylation system, suggesting that LRPPRC levels determine the nature of the biochemical phenotype. We tested this hypothesis in cultured muscle cells and tissues from LSFC patients. LRPPRC levels were reduced in LSFC muscle cells, resulting in combined complex I and IV deficiencies. A similar combined deficiency was observed in skeletal muscle. Complex IV was only moderately reduced in LSFC heart, but was almost undetectable in liver. Both of these tissues showed elevated levels of complexes I and III. Despite the marked biochemical differences, the steady-state levels of LRPPRC and mitochondrial mRNAs were extremely low, LRPPRC was largely detergent-insoluble, and SLIRP was undetectable in all LSFC tissues. The level of the LRPPRC/SLIRP complex appeared much reduced in control tissues by the first dimension blue-native polyacrylamide gel electrophoresis (BN-PAGE) analysis compared with fibroblasts, and even by second dimension analysis it was virtually undetectable in control heart. These results point to tissue-specific pathways for the post-transcriptional handling of mitochondrial mRNAs and suggest that the biochemical defects in LSFC reflect the differential ability of tissues to adapt to the mutation. PMID:25214534

  4. Genome-Wide Association Study of Lung Function Phenotypes in a Founder Population

    PubMed Central

    Yao, Tsung-Chieh; Du, Gaixin; Han, Lide; Sun, Ying; Hu, Donglei; Yang, James J.; Mathias, Rasika; Roth, Lindsey A.; Rafaels, Nicholas; Thompson, Emma E.; Loisel, Dagan A.; Anderson, Rebecca; Eng, Celeste; Orbegozo, Maitane Arruabarrena; Young, Melody; Klocksieben, James M.; Anderson, Elizabeth; Shanovich, Kathleen; Lester, Lucille A.; Williams, L. Keoki; Barnes, Kathleen C.; Burchard, Esteban G.; Nicolae, Dan L.; Abney, Mark; Ober, Carole

    2014-01-01

    Background Lung function is a long-term predictor of mortality and morbidity. Objective We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. Methods We performed a genome-wide association study (GWAS) of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC in 1,144 Hutterites aged 6–89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation (LASSO) regression to select the minimum set of SNPs that best predict FEV1/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs. Results Our GWAS identified significant associations between FEV1/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7x10−8 ~ 3.4x10−9). Nine SNPs at or near four additional loci had P-values < 10−5 with FEV1/FVC. There were only two SNPs with P-values < 10−5 for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, six loci were identified that had a significant degree of functional connectivity (GRAIL P < 0.05), including three clusters of β-defensin genes, two chemokine genes (CCL18 and CXCL12), and TNFRSF13B. Conclusion This study identifies genome-wide significant associations and replicates results of previous GWAS. Multimarker modeling implicated for the first time common variation in genes involved in anti-microbial immunity in airway mucosa influences lung function. PMID:23932459

  5. Comprehensive Characterization of the Transmitted/founder env Genes from a Single MSM Cohort in China

    PubMed Central

    Chen, Yue; Li, Ning; Zhang, Tong; Huang, Xiaojie; Cai, Fangping; Vandergrift, Nathan; Xin, Ruolei; Meng, Zhefeng; Zhang, Xiaoyan; Jiang, Chunlai; Xu, Xiaoning; Montefiori, David C; Gao, Feng; Wu, Hao

    2015-01-01

    Background The men having sex with men (MSM) population has become one of major risk groups for HIV-1 infection in China. However, the epidemiological patterns, function of the env genes, and autologous and heterologous neutralization activity in the same MSM population have not been systematically characterized. Methods The env gene sequences were obtained by the single genome amplification (SGA). The time to the most recent common ancestor (tMRCA) was estimated for each genotype using the Bayesian MCMC approach. Coreceptor usage was determined in NP-2 cells. Neutralization was analyzed using Env pseudoviruses in TZM-bl cells. Results We have obtained 547 full-length env gene sequences by SGA from 30 acute/early HIV-1-infected individuals in the Beijing MSM cohort. Three genotypes (Subtype B, CRF01_AE, and CRF07_BC) were identified and 20% of the individuals were infected with multiple transmitted/founder (T/F) viruses. The tight clusters of the MSM sequences regardless of geographic origins indicated nearly exclusive transmission within the MSM population and limited number of introductions. The tMRCA for each genotype was 10-15 years after each was first introduced in China. Disparate preferences for coreceptor usages among three genotypes might lead to the changes in percentage of different genotypes in the MSM population over time. The genotype-matched and -mismatched neutralization activity varied among the three genotypes. Conclusions Identification of unique characteristics for transmission, coreceptor usage, neutralization profile and epidemic patterns of HIV-1 is critical for the better understanding of transmission mechanisms, development of preventive strategies, and evaluation of vaccine efficacy in the MSM population in China. PMID:25886933

  6. The Significance of Genetic Polymorphisms within and between Founder Populations of Ceratitis capitata (Wied.) from Argentina

    PubMed Central

    Basso, Alicia; Martinez, Laura; Manso, Fanny

    2009-01-01

    Background The Mediterranean fruit fly Ceratitis Capitata (DIPTERA: Tephritidae) is a major agricultural pest in Argentina. One main cause for the success of non-contaminant control programs based on genetic strategies is compatibility between natural and laboratory germplasms. A comprehensive characterization of the fruit fly based on genetic studies and compatibility analysis was undertaken on two founder populations from the provinces of Buenos Aires and Mendoza, used in pioneering sterile male technique control programmes in our country. The locations are 1,000 km apart from each other. Methodology/Principal Findings We compared the genetic composition of both populations based on cytological, physiological and morphological characterization. Compatibility studies were performed in order to determine the presence of isolation barriers. Results indicate that the Buenos Aires germplasm described previously is partially different from that of the Mendoza population. Both laboratory colonies are a reservoir of mutational and cytological polymorphisms. Some sexual chromosome variants such as the XL and the YL resulting from attachment of a B-chromosome to the X-chromosome or Y-chromosome behave as a lethal sex-linked factor. Our results also show incompatibility between both germplasms and pre-zygotic isolation barriers between them. Our evidence is consistent with the fact that polymorphisms are responsible for the lack of compatibility. Conclusions The genetic control mechanism should be directly produced in the germplasm of the target population in order to favour mating conditions. This is an additional requirement for the biological as well as economic success of control programs based on genetic strategies such as the sterile insect technique. The analysis of representative samples also revealed natural auto-control mechanisms which could be used in modifying pest population dynamics. PMID:19252742

  7. HIV competition dynamics over sexual networks: first comer advantage conserves founder effects.

    PubMed

    Ferdinandy, Bence; Mones, Enys; Vicsek, Tamás; Müller, Viktor

    2015-02-01

    Outside Africa, the global phylogeography of HIV is characterized by compartmentalized local epidemics that are typically dominated by a single subtype, which indicates strong founder effects. We hypothesized that the competition of viral strains at the epidemic level may involve an advantage of the resident strain that was the first to colonize a population. Such an effect would slow down the invasion of new strains, and thus also the diversification of the epidemic. We developed a stochastic modelling framework to simulate HIV epidemics over dynamic contact networks. We simulated epidemics in which the second strain was introduced into a population where the first strain had established a steady-state epidemic, and assessed whether, and on what time scale, the second strain was able to spread in the population. Simulations were parameterized based on empirical data; we tested scenarios with varying levels of overall prevalence. The spread of the second strain occurred on a much slower time scale compared with the initial expansion of the first strain. With strains of equal transmission efficiency, the second strain was unable to invade on a time scale relevant for the history of the HIV pandemic. To become dominant over a time scale of decades, the second strain needed considerable (>25%) advantage in transmission efficiency over the resident strain. The inhibition effect was weaker if the second strain was introduced while the first strain was still in its growth phase. We also tested how possible mechanisms of interference (inhibition of superinfection, depletion of highly connected hubs in the network, one-time acute peak of infectiousness) contribute to the inhibition effect. Our simulations confirmed a strong first comer advantage in the competition dynamics of HIV at the population level, which may explain the global phylogeography of the virus and may influence the future evolution of the pandemic. PMID:25654450

  8. Counting the Founders: The Matrilineal Genetic Ancestry of the Jewish Diaspora

    PubMed Central

    Behar, Doron M.; Metspalu, Ene; Kivisild, Toomas; Rosset, Saharon; Tzur, Shay; Hadid, Yarin; Yudkovsky, Guennady; Rosengarten, Dror; Pereira, Luisa; Amorim, Antonio; Kutuev, Ildus; Gurwitz, David; Bonne-Tamir, Batsheva; Villems, Richard; Skorecki, Karl

    2008-01-01

    The history of the Jewish Diaspora dates back to the Assyrian and Babylonian conquests in the Levant, followed by complex demographic and migratory trajectories over the ensuing millennia which pose a serious challenge to unraveling population genetic patterns. Here we ask whether phylogenetic analysis, based on highly resolved mitochondrial DNA (mtDNA) phylogenies can discern among maternal ancestries of the Diaspora. Accordingly, 1,142 samples from 14 different non-Ashkenazi Jewish communities were analyzed. A list of complete mtDNA sequences was established for all variants present at high frequency in the communities studied, along with high-resolution genotyping of all samples. Unlike the previously reported pattern observed among Ashkenazi Jews, the numerically major portion of the non-Ashkenazi Jews, currently estimated at 5 million people and comprised of the Moroccan, Iraqi, Iranian and Iberian Exile Jewish communities showed no evidence for a narrow founder effect, which did however characterize the smaller and more remote Belmonte, Indian and the two Caucasus communities. The Indian and Ethiopian Jewish sample sets suggested local female introgression, while mtDNAs in all other communities studied belong to a well-characterized West Eurasian pool of maternal lineages. Absence of sub-Saharan African mtDNA lineages among the North African Jewish communities suggests negligible or low level of admixture with females of the host populations among whom the African haplogroup (Hg) L0-L3 sub-clades variants are common. In contrast, the North African and Iberian Exile Jewish communities show influence of putative Iberian admixture as documented by mtDNA Hg HV0 variants. These findings highlight striking differences in the demographic history of the widespread Jewish Diaspora. PMID:18446216

  9. Genetic conditions among Canadian Mennonites: evidence for a founder effect among the old colony (Chortitza) Mennonites.

    PubMed

    Jaworski, M A; Severini, A; Mansour, G; Konrad, H M; Slater, J; Hennig, K; Schlaut, J; Yoon, J W; Pak, C Y; Maclaren, N

    1989-04-01

    Distinctive disease patterns exist among Canadian Old Colony (Chortitza) Mennonites. This religious and genetic isolate is of 16th century Dutch/German ancestry. The group originated in the Netherlands, then settled in the Vistula delta area of western Prussia for 200 years. A small number of founding families later migrated to Chortitza, the "Old Colony", in the Ukraine in the late 18th/early 19th century, where they remained a distinct genetic isolate. This group has come to Canada over the past 100 years. The more conservative Canadian Mennonites of Chortitza descent practice strict endogamy, have a large family size and live predominantly in rural public health subdistricts in the four western provinces, and in southern Ontario. The world's largest reported familial aggregations of insulin-dependent diabetes mellitus, of autoimmune diseases and of Tourette syndrome were initially ascertained in a small northern Alberta public health subdistrict. Clusterings of malformations, inborn errors of metabolism, and other conditions were also found in the subdistrict, and in group descendents living in other provinces. A founder effect, or genetic drift, accounts for the familial aggregations of autosomal recessive and dominant conditions, some diseases of multifactorial determination, and other inherited conditions in Canadian kinships descending from this ancestral group. The medical literature on genetic conditions among Canadian Mennonites is reviewed and re-evaluated in the light of this information. There is biochemical, serologic, and molecular biologic evidence in favour of genetic homogeneity amongst patients with certain inherited conditions in this special population group. This genetic isolate offers potential for the study of the genetic epidemiology and molecular biology of inherited diseases. A computerized genealogic data base on about 1400 group members, as well as a cryopreserved lymphocyte/DNA bank on over 100 individuals with genetic conditions has

  10. Microsatellites haplotyping of CF chromosomes shows linkage disequilibrium and several founder effects in Brittany (France)

    SciTech Connect

    Raguenes, O.; Ferec, C.; Mercier, B.

    1994-09-01

    A large study on cystic fibrosis (CF) is underway in Brittany (France). It is based on 902 CF patients distributed in 795 families who were or are still followed at the {open_quotes}Centre Helio-Marin{close_quotes} in Roscoff and/or were subjected to a molecular analysis at the {open_quotes}Centre de Biogenetique{close_quotes} in Brest. At present, the CF mutations have been identified in 309 patients born in Brittany, most of them of Celtic origin. A microsatellite (MS) study using IVS 17b TA, IVS 17b CA and IVS 8 CA was also completed in 63 CF patients and their parents (carriers of the {Delta}F508 mutation or the G551D mutation or the 1078delT mutation or the W846X mutation). All the 21 chromosomes carrying the 1078delT mutation had the same MS haplotype (16-21-13), which was also found on 9 of the 83 non-CF chromosomes analyzed. All the 16 chromosomes with the G551D mutation carried another MS haplotype (16-7-17), which was also found on 13.3% of the non-CF chromosomes. All the 6 chromosomes with the W846X mutation carried the 16-32-13 haplotype, also found on 6.0% of the non-CF chromosomes. Sixteen different MS haplotypes were found among the 74 chromosomes carrying the{Delta}F508 mutation, three of them representing 74.3% (55/74) of the chromosomes. These were the 23-31-13 haplotype (31/74 - 41.9%), the 17-31-13 haplotype (11/74 - 14.9%), and the 17-32-13 haplotype (13/74 - 17.6%). These results show that the CF mutations observed in Brittany are in linkage disequilibrium with the MS haplotypes. They also suggest that their presence in Brittany is the consequence of several founder effects.

  11. The Expression of TALEN before Fertilization Provides a Rapid Knock-Out Phenotype in Xenopus laevis Founder Embryos

    PubMed Central

    Suzuki, Miyuki; Sakane, Yuto; Sakuma, Tetsushi; Herberg, Sarah; Simeone, Angela; Simpson, David; Jullien, Jerome; Yamamoto, Takashi; Gurdon, J. B.

    2015-01-01

    Recent advances in genome editing using programmable nucleases have revolutionized gene targeting in various organisms. Successful gene knock-out has been shown in Xenopus, a widely used model organism, although a system enabling less mosaic knock-out in founder embryos (F0) needs to be explored in order to judge phenotypes in the F0 generation. Here, we injected modified highly active transcription activator-like effector nuclease (TALEN) mRNA to oocytes at the germinal vesicle (GV) stage, followed by in vitro maturation and intracytoplasmic sperm injection, to achieve a full knock-out in F0 embryos. Unlike conventional injection methods to fertilized embryos, the injection of TALEN mRNA into GV oocytes allows expression of nucleases before fertilization, enabling them to work from an earlier stage. Using this procedure, most of developed embryos showed full knock-out phenotypes of the pigmentation gene tyrosinase and/or embryonic lethal gene pax6 in the founder generation. In addition, our method permitted a large 1 kb deletion. Thus, we describe nearly complete gene knock-out phenotypes in Xenopus laevis F0 embryos. The presented method will help to accelerate the production of knock-out frogs since we can bypass an extra generation of about 1 year in Xenopus laevis. Meantime, our method provides a unique opportunity to rapidly test the developmental effects of disrupting those genes that do not permit growth to an adult able to reproduce. In addition, the protocol shown here is considerably less invasive than the previously used host transfer since our protocol does not require surgery. The experimental scheme presented is potentially applicable to other organisms such as mammals and fish to resolve common issues of mosaicism in founders. PMID:26580070

  12. Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis.

    PubMed

    Bu, Rong; Siraj, Abdul K; Al-Obaisi, Khadija A S; Beg, Shaham; Al Hazmi, Mohsen; Ajarim, Dahish; Tulbah, Asma; Al-Dayel, Fouad; Al-Kuraya, Khawla S

    2016-09-01

    Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, nine different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p = 0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost-effective screening strategy. PMID:27082205

  13. Foundering of lower island-arc crust as an explanation for the origin of the continental Moho.

    PubMed

    Jagoutz, Oliver; Behn, Mark D

    2013-12-01

    A long-standing theory for the genesis of continental crust is that it is formed in subduction zones. However, the observed seismic properties of lower crust and upper mantle in oceanic island arcs differ significantly from those in the continental crust. Accordingly, significant modifications of lower arc crust must occur, if continental crust is indeed formed from island arcs. Here we investigate how the seismic characteristics of arc crust are transformed into those of the continental crust by calculating the density and seismic structure of two exposed sections of island arc (Kohistan and Talkeetna). The Kohistan crustal section is negatively buoyant with respect to the underlying depleted upper mantle at depths exceeding 40 kilometres and is characterized by a steady increase in seismic velocity similar to that observed in active arcs. In contrast, the lower Talkeetna crust is density sorted, preserving only relicts (about ten to a hundred metres thick) of rock with density exceeding that of the underlying mantle. Specifically, the foundering of the lower Talkeetna crust resulted in the replacement of dense mafic and ultramafic cumulates by residual upper mantle, producing a sharp seismic discontinuity at depths of around 38 to 42 kilometres, characteristic of the continental Mohorovičić discontinuity (the Moho). Dynamic calculations indicate that foundering is an episodic process that occurs in most arcs with a periodicity of half a million to five million years. Moreover, because foundering will continue after arc magmatism ceases, this process ultimately results in the formation of the continental Moho. PMID:24305163

  14. The Unseen Founders Of Quaternary Science - The Men Of Glasgow, Scotland (Invited)

    NASA Astrophysics Data System (ADS)

    Rose, J.

    2010-12-01

    Louis Agassiz (1807-1873) and Charles Lyell (1797-1875) are widely regarded as the founders of Quaternary Science, and there is no doubt that they played their part: Agassiz in 1840 presented and promoted his case for the wide-scale fluctuations of glaciers, and Lyell, through his books and contacts, did much to introduce the subject which we now know as climate change. However there are a number of individuals who contributed to the founding of Quaternary Science who are not so readily recognised and a remarkable fact is that a significant proportion were men without academic training or background who come from, or worked in Glasgow or the adjacent region of central Scotland. First amongst the Glaswegians was James Smith (1782-1867) who, in 1836 presented a paper to the Geological Society of London (where it was duly ignored) in which he suggested, on the basis of fossils dredged from the bed of the Clyde and experience of sailing around Iceland, that the climate of Scotland had been as cold as that of Iceland in the recent past. In 1841, Charles Maclaren (1782-1866) a journalist from Edinburgh, but using information based on raised shorelines near Glasgow proposed what we now know as the glacio-eustatic theory in which the variations in glacier extent control the level of the sea. Perhaps the most important of all was James Croll (1821- 1890) who worked on the theory of ice ages, based on orbital forcing, while janitor at the Andersonian Institute and Museum in Glasgow between 1859-1867. This work was the true precursor to the Milankovitch theory which provides the explanation for the major predictable elements of climate change. Robert Jack (1845-1921) from Irvine, southwest of Glasgow, while doing fieldwork for the British Geological Survey near Loch Lomond close to Glasgow, described in 1874 evidence for non-glacial conditions between tills and clearly recognised that climate could change from glacial to temperate and then glacial climate, before returning to

  15. Founder-cell-specific transcription of the DORNRÖSCHEN-LIKE promoter and integration of the auxin response.

    PubMed

    Comelli, Petra; Glowa, Dorothea; Chandler, John W; Werr, Wolfgang

    2016-01-01

    Transcription of the DORNRÖSCHEN (DRNL) promoter marks lateral-organ founder cells throughout Arabidopsis development, from cotyledons to flowers or floral organs. In the inflorescence apex, DRNL::GFP depicts incipient floral phyllotaxy, and organs in the four floral whorls are differentially prepatterned: the sepals unidirectionally along an abaxial-adaxial axis, the four petals and two lateral stamens in two putative morphogenetic fields, and the medial stamens subsequently in a ring-shaped domain, before two groups of carpel founder cells are specified. The dynamic DRNL transcription pattern is controlled by three enhancer elements, which redundantly and synergistically control qualitative or quantitative aspects of expression, and differentially integrate the auxin response in Arabidopsis inflorescence and floral meristems. The high sequence conservation of all three enhancer elements among the Brassicaceae is striking, which suggests that densely packed cis-regulatory elements are conserved to recruit multiple transcription factors, including auxin response factors, into higher-order enhanceosome complexes. The spatial organization of the enhancers is also conserved, by a microsynteny that extends beyond the Brassicaceae, which relates to enhancer sharing, as the distal element En1 bidirectionally serves DRNL and the upstream At1g24600 gene; the genes are transcribed in opposite directions and possibly comprise a conserved functional chromatin domain. PMID:26428063

  16. A Population-Based Study of Autosomal-Recessive Disease-Causing Mutations in a Founder Population

    PubMed Central

    Chong, Jessica X.; Ouwenga, Rebecca; Anderson, Rebecca L.; Waggoner, Darrel J.; Ober, Carole

    2012-01-01

    The decreasing cost of whole-genome and whole-exome sequencing has resulted in a renaissance for identifying Mendelian disease mutations, and for the first time it is possible to survey the distribution and characteristics of these mutations in large population samples. We conducted carrier screening for all autosomal-recessive (AR) mutations known to be present in members of a founder population and revealed surprisingly high carrier frequencies for many of these mutations. By utilizing the rich demographic, genetic, and phenotypic data available on these subjects and simulations in the exact pedigree that these individuals belong to, we show that the majority of mutations were most likely introduced into the population by a single founder and then drifted to the high carrier frequencies observed. We further show that although there is an increased incidence of AR diseases overall, the mean carrier burden is likely to be lower in the Hutterites than in the general population. Finally, on the basis of simulations, we predict the presence of 30 or more undiscovered recessive mutations among these subjects, and this would at least double the number of AR diseases that have been reported in this isolated population. PMID:22981120

  17. Consanguinity and founder effect for Gaucher disease mutation G377S in a population from Tabuleiro do Norte, Northeastern Brazil.

    PubMed

    Chaves, R G; Pereira, L da Veiga; de Araújo, F T; Rozenberg, R; Carvalho, M D F; Coelho, J C; Michelin-Tirelli, K; Chaves, M de Freitas; Cavalcanti, G B

    2015-10-01

    Gaucher's disease (GD) is caused by a β-glucocerebrosidase deficiency, leading to the accumulation of glucocerebroside in the reticuloendothelial system. The prevalence of GD in Tabuleiro do Norte (TN) (1:4000) is the highest in Brazil. The purpose of this study was to present evidence of consanguinity and founder effect for the G377S mutation (c.1246G>A) among GD patients in TN based on enzyme, molecular and genealogical studies. Between March 2009 and December 2010, 131 subjects at risk for GD (GC in dried blood ≤2.19 nmol/h/ml) and 5 confirmed GD patients from the same community were submitted for molecular analysis to characterize the genetic profile of the population. Based on the enzymatic and molecular analysis, the subjects were classified into three categories: affected (n = 5), carrier (n = 20) and non-carrier (n = 111). All carriers were (G377S/wt). Affected subjects were homozygous (G377S/G377S). The identification of a single mutation in carriers and homozygotes from different generations, the history of the community and the genealogy study suggest that the high prevalence of GD in this population may be due to a combination of consanguinity and founder effect for the G377S mutation. PMID:25287185

  18. High frequency of BRCA1, but not CHEK2 or NBS1 (NBN), founder mutations in Russian ovarian cancer patients

    PubMed Central

    Suspitsin, Evgeny N; Sherina, Nathalia Yu; Ponomariova, Daria N; Sokolenko, Anna P; Iyevleva, Aglaya G; Gorodnova, Tatyana V; Zaitseva, Olga A; Yatsuk, Olga S; Togo, Alexandr V; Tkachenko, Nathalia N; Shiyanov, Grigory A; Lobeiko, Oksana S; Krylova, Nadezhda Yu; Matsko, Dmitry E; Maximov, Sergey Ya; Urmancheyeva, Adel F; Porhanova, Nathalia V; Imyanitov, Evgeny N

    2009-01-01

    Background A significant portion of ovarian cancer (OC) cases is caused by germ-line mutations in BRCA1 or BRCA2 genes. BRCA testing is cheap in populations with founder effect and therefore recommended for all patients with OC diagnosis. Recurrent mutations constitute the vast majority of BRCA defects in Russia, however their impact in OC morbidity has not been yet systematically studied. Furthermore, Russian population is characterized by a relatively high frequency of CHEK2 and NBS1 (NBN) heterozygotes, but it remains unclear whether these two genes contribute to the OC risk. Methods The study included 354 OC patients from 2 distinct, geographically remote regions (290 from North-Western Russia (St.-Petersburg) and 64 from the south of the country (Krasnodar)). DNA samples were tested by allele-specific PCR for the presence of 8 founder mutations (BRCA1 5382insC, BRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, BRCA2 6174delT, CHEK2 1100delC, CHEK2 IVS2+1G>A, NBS1 657del5). In addition, literature data on the occurrence of BRCA1, BRCA2, CHEK2 and NBS1 mutations in non-selected ovarian cancer patients were reviewed. Results BRCA1 5382insC allele was detected in 28/290 (9.7%) OC cases from the North-West and 11/64 (17.2%) OC patients from the South of Russia. In addition, 4 BRCA1 185delAG, 2 BRCA1 4153delA, 1 BRCA2 6174delT, 2 CHEK2 1100delC and 1 NBS1 657del5 mutation were detected. 1 patient from Krasnodar was heterozygous for both BRCA1 5382insC and NBS1 657del5 variants. Conclusion Founder BRCA1 mutations, especially BRCA1 5382insC variant, are responsible for substantial share of OC morbidity in Russia, therefore DNA testing has to be considered for every OC patient of Russian origin. Taken together with literature data, this study does not support the contribution of CHEK2 in OC risk, while the role of NBS1 heterozygosity may require further clarification. PMID:19338682

  19. Impact on electroencephalography of Adolf Beck, a prominent Polish scientist and founder of the Lviv School of Physiology.

    PubMed

    Zayachkivska, Oksana; Gzhegotsky, Mechyslav; Coenen, Anton

    2012-07-01

    Adolf Beck (1863-1942) can be regarded as the co-founder of electroencephalography. His studies on the cerebral cortex of animals have facilitated the introduction of the electroencephalogram (EEG) as a main tool for studying the brain. The localization of senses on the cortex with evoked potentials and the description of the desynchronization of the electrical brain activity upon stimulation, are hallmarks of the research of Beck. He performed his groundbreaking studies under supervision of the famous Napoleon Cybulski at the Jagiellonian University in Cracow (Poland) between 1888 and 1895. In that last year Beck was appointed professor at the University of Lemberg (Lviv), where he founded the Department of Physiology and recruited scientists to the Lviv School of Physiology. Beck was the leading authority of the University of Lemberg in the most turbulent period of the town's history. Together with Cybulski he wrote the influential textbook 'Human physiology' in 1915. PMID:22101137

  20. Dynamics of recombinant hG-CSF in transgenic goat: preliminary study in the founder during hormonally induced lactation.

    PubMed

    Moura, Raylene R; Albuquerque, Erica S; Melo, Carlos Henrique S; Alcântara-Neto, Agostinho S; Batista, Ribrio Ivan T P; Nunes-Pinheiro, Diana Célia S; Pereira, Alexsandra F; Teixeira, Darcio Ítalo A; Melo, Luciana M; Serova, Irina A; Andreeva, Lyudmila E; Serov, Oleg L; Freitas, Vicente José F

    2013-01-01

    This study aimed to characterize the dynamic of human granulocyte colony-stimulating factor (hG-CSF) during artificial lactation in a transgenic founder goat and to assess its potential ectopic expression and health. The female secreted 93.9 to 1,474.6 µg hG-CSF per mL of milk. Two peaks of serum hG-CSF (3,470 and 7,390 pg/mL) were detected in the first half of the lactation. Outside of the lactation, hG-CSF was absent from serum, indicating no ectopic expression. During the treatment to induce lactation, transgenic female presented increased neutrophil and lymphocyte blood counts when compared to nontransgenic female. Despite transient neutrophilia, serum biochemistry profiles indicated normal liver and renal functions. Thus, transgenic goat expressed hG-CSF in quantities sufficient for a commercial bioreactor and remained clinically healthy. PMID:23394365

  1. The history of the German Cardiac Society and the American College of Cardiology and their two founders.

    PubMed

    Lüderitz, Berndt; Holmes, David R; Harold, John

    2013-02-26

    The German Cardiac Society is the oldest national cardiac society in Europe, founded on June 3, 1927, in Bad Nauheim by Dr. Bruno Kisch and Professor Arthur Weber. They were actively supported by Dr. Franz Groedel, who together with Kisch became co-founders of the American College of Cardiology in 1949. Both Groedel and Kisch would be proud to see the fulfillment of their visions and dreams, which was commemorated at the joint session of the two societies held during the 78th annual meeting of the German Cardiac Society in Mannheim, Germany. "It is ironic that their dreadful years in Germany and their loss to German Cardiology helped to contribute to advances in American and international Cardiology," said Dr. Simon Dack, American College of Cardiology president in 1956 and 1957. The legacy of Groedel might be reflected by his own words: "We will meet the future not merely by dreams but by concerned action and inextinguishable enthusiasm". PMID:23428213

  2. Mitochondrial Genome Diversity of Native Americans Supports a Single Early Entry of Founder Populations into America

    PubMed Central

    Silva Jr., Wilson A.; Bonatto, Sandro L.; Holanda, Adriano J.; Ribeiro-dos-Santos, Andrea K.; Paixão, Beatriz M.; Goldman, Gustavo H.; Abe-Sandes, Kiyoko; Rodriguez-Delfin, Luis; Barbosa, Marcela; Paçó-Larson, Maria Luiza; Petzl-Erler, Maria Luiza; Valente, Valeria; Santos, Sidney E. B.; Zago, Marco A.

    2002-01-01

    There is general agreement that the Native American founder populations migrated from Asia into America through Beringia sometime during the Pleistocene, but the hypotheses concerning the ages and the number of these migrations and the size of the ancestral populations are surrounded by controversy. DNA sequence variations of several regions of the genome of Native Americans, especially in the mitochondrial DNA (mtDNA) control region, have been studied as a tool to help answer these questions. However, the small number of nucleotides studied and the nonclocklike rate of mtDNA control-region evolution impose several limitations to these results. Here we provide the sequence analysis of a continuous region of 8.8 kb of the mtDNA outside the D-loop for 40 individuals, 30 of whom are Native Americans whose mtDNA belongs to the four founder haplogroups. Haplogroups A, B, and C form monophyletic clades, but the five haplogroup D sequences have unstable positions and usually do not group together. The high degree of similarity in the nucleotide diversity and time of differentiation (i.e., ∼21,000 years before present) of these four haplogroups support a common origin for these sequences and suggest that the populations who harbor them may also have a common history. Additional evidence supports the idea that this age of differentiation coincides with the process of colonization of the New World and supports the hypothesis of a single and early entry of the ancestral Asian population into the Americas. PMID:12022039

  3. A founder mutation in Artemis, an SNM1-like protein, causes SCID in Athabascan-speaking Native Americans.

    PubMed

    Li, Lanying; Moshous, Despina; Zhou, Yungui; Wang, Junhua; Xie, Gang; Salido, Eduardo; Hu, Diana; de Villartay, Jean-Pierre; Cowan, Morton J

    2002-06-15

    Athabascan SCID (SCIDA) is an autosomal recessive disorder found among Athabascan-speaking Native Americans and is manifested by the absence of both T and B cells (T(-)B(-)NK(+) SCID). We previously mapped the SCIDA gene to a 6.5-cM interval on chromosome 10p. SCIDA fibroblasts were found to have defective coding joint and reduced, but precise signal joint formation during V(D)J recombination. After excluding potential candidate genes, we conducted a combined positional candidate and positional cloning approach leading to the identification of nine novel transcripts in the refined SCIDA region. One of the transcripts showed significant homology with the mouse and yeast SNM1/PSO(2) and was recently reported (Artemis) to be responsible for another T(-)B(-)NK(+) SCID condition (radiation sensitive SCID) in 13 patients of primarily European origin. In our evaluation of this gene, we have identified a unique nonsense mutation in 21 SCIDA patients that is closely correlated to the founder haplotypes that we had previously identified. This nonsense founder mutation results in the truncation of the deduced protein product. The wild-type construct of the primary transcript can effectively complement the defective coding joint and reduced signal joint formation in SCIDA fibroblasts. The above results indicate that this SNM1-like gene (Artemis) is the gene responsible for SCIDA. We also discovered three additional alternative exons and detected at least six alternatively spliced SCIDA variants (SCIDA-V1, 2, 3, 4, 5, and 6) coexisting with the primary transcript in trace amounts. Finally, we found that the SCIDA primary transcript (Artemis) encodes a nuclear protein. PMID:12055248

  4. 500th birthday of Andreas Vesalius, the founder of modern anatomy: "vivitur ingenio, caetera mortis erunt" ("genius lives on, all else is mortal").

    PubMed

    Hadzic, Admir; Sadeghi, Neda; Vandepitte, Catherine; Vandepitte, Walter; Van de Velde, Marc; Hadzic, Alen; Van Robays, Johan; Heylen, Rene; Herijgers, Paul; Vloka, Caroline; Van Zundert, Jan

    2014-01-01

    It is often said that regional anesthesia is the practice of applied anatomy. Therefore, it is fitting that on the occasion of his 500th birthday, we celebrate the life and work of the brilliant Flemish anatomist, Andreas Vesalius (1514-1564), the founder of modern anatomy. PMID:25340483

  5. A Bundle of Silences: Examining the Racial Representation of Black Founding Fathers of the United States through Glenn Beck's "Founders' Fridays"

    ERIC Educational Resources Information Center

    King, LaGarrett J.; Womac, Patrick

    2014-01-01

    This article explores the discourse on Black Founding Fathers through Glenn Beck's television show, "Founders' Fridays". According to Beck, this 2010 summer television special was an opportunity to present Black American history in a more nuanced and truthful way. The theoretical framework, silencing the past, is used to…

  6. HealthSouth's most wanted. Founder and former chairman and CEO Richard Scrushy is indicted for 85 counts of conspiracy, fraud and money laundering.

    PubMed

    Piotrowski, Julie

    2003-11-10

    Wake-up call for the industry or an isolated case of corporate chicanery? Healthcare experts are divided on the import of Richard Scrushy's indictment on 85 counts last week in connection with the financial scandal at HealthSouth Corp. The indictment alleges the company founder relied on electronic and telephone surveillance, threats and intimidation to control his accomplices. PMID:14666542

  7. Colleges and Universities as Historic Institutions: a Study of the Historical Context of Campus Architecture: Founders Hall, Virginia Commonwealth University, Richmond, Virginia.

    ERIC Educational Resources Information Center

    Shultz, James A.

    A study of Founders Hall at the Virginia Commonwealth University (VCU) explores the history of that building and its symbolic role for the campus and the institution. The building was originally a residence built in the late 19th century and was later the location of the Richmond School of Social Work and Public Policy and of the Richmond…

  8. Very low microsatellite polymorphism and large heterozygote deficits suggest founder effects and cryptic structure in the parasite Perkinsus olseni.

    PubMed

    Vilas, Román; Cao, Asunción; Pardo, Belén G; Fernández, Sergio; Villalba, Antonio; Martínez, Paulino

    2011-07-01

    Twelve microsatellite markers were used to characterize 130 clonal cultures of Perkinsus olseni derived from 30 clams from six different geographic locations. Only two loci were polymorphic in the four populations studied from Spanish coast (mean sample size = 31.2), and a third locus was variable in only two populations. In contrast, five parasites isolated from five clams from Japan and New Zealand showed variation at nine loci. Low genetic variation (2.08 ± 0.64 alleles per locus; mean genetic diversity: 0.101 ± 0.022), and very high F(IS) values (0.857 on average) were observed in Spanish populations. A total of 39 multilocus genotypes (MLGs) were identified in the whole sample (121 clonal isolates after excluding incomplete MLGs due to missing data). A three-level hierarchical analysis of molecular variance found significant levels of genetic variation within infrapopulations (all the parasites in a single host; Φ(IS) = 0.679) and among infrapopulations within the component population (all the parasites among a host population; Φ(SC) = 0.579). Differences among the component population from different geographic locations were not significant (Φ(CT) = 0.057). These results suggest that an important fraction of F(IS) is explained by the Wahlund effect, but also strong inbreeding within infrapopulations. Another explanation for the high F(IS) within infrapopulations is the presence of haploid and diploid stages in the clam. Although fully aquatic system provides many opportunities for mixing of parasites from different clams, results are consistent with the consideration of all P. olseni in a clam as a cohesive genetic unit (i.e., deme). If the parasite was introduced into the Spanish coast with the importation of infected clams from Asia and Oceania, the low microsatellite polymorphism could be reflecting founder effects in the recent evolutionary history of P. olseni. The loss of alleles would be intensified in a scenario structured in numerous demes

  9. Nonsyndromic retinitis pigmentosa is highly prevalent in the Jerusalem region with a high frequency of founder mutations

    PubMed Central

    Banin, Eyal

    2015-01-01

    Purpose Nonsyndromic retinitis pigmentosa (RP) is the most common inherited retinal degeneration, and prevalence of the disease has been reported in populations of American and European origin with a relatively low consanguinity rate. Our aim was to determine the prevalence of nonsyndromic RP in the Jerusalem region, which has a population of about 1 million individuals with a high rate of consanguinity. Methods The patients’ clinical data included eye exam findings (visual acuity, anterior segment, and funduscopy) as well as electroretinographic (ERG) testing results under scotopic and photopic conditions. Mutation analysis on a subgroup of patients was performed mainly with candidate gene analysis and homozygosity mapping. Results We evaluated the medical records of patients with degenerative retinal diseases residing in the Jerusalem region who were examined over the past 20 years in a large tertiary medical center. A total of 453 individuals affected with nonsyndromic RP were diagnosed at our center, according to funduscopic findings and ERG testing. Based on the estimated population size of 945,000 individuals who reside in the vicinity of Jerusalem, the prevalence of nonsyndromic RP in this region is 1:2,086. The prevalence of RP was higher among Arab Muslims (1:1,798) compared to Jews (1:2,230), mainly due to consanguineous marriages that are more common in the Arab Muslim population. To identify the genetic causes of RP in our cohort, we recruited 383 patients from 183 different families for genetic analysis: 70 with autosomal recessive (AR) inheritance, 15 with autosomal dominant, 86 isolate cases, and 12 with an X-linked inheritance pattern. In 64 (35%) of the families, we identified the genetic cause of the disease, and we revised the inheritance pattern of 20 isolate cases to the AR pattern; 49% of the families in our cohort had AR inheritance. Interestingly, in 42 (66%) of the genetically identified families, the cause of disease was a founder

  10. Genetic basis of transcriptome differences between the founder strains of the rat HXB/BXH recombinant inbred panel

    PubMed Central

    2012-01-01

    Background With the advent of next generation sequencing it has become possible to detect genomic variation on a large scale. However, predicting which genomic variants are damaging to gene function remains a challenge, as knowledge of the effects of genomic variation on gene expression is still limited. Recombinant inbred panels are powerful tools to study the cis and trans effects of genetic variation on molecular phenotypes such as gene expression. Results We generated a comprehensive inventory of genomic differences between the two founder strains of the rat HXB/BXH recombinant inbred panel: SHR/OlaIpcv and BN-Lx/Cub. We identified 3.2 million single nucleotide variants, 425,924 small insertions and deletions, 907 copy number changes and 1,094 large structural genetic variants. RNA-sequencing analyses on liver tissue of the two strains identified 532 differentially expressed genes and 40 alterations in transcript structure. We identified both coding and non-coding variants that correlate with differential expression and alternative splicing. Furthermore, structural variants, in particular gene duplications, show a strong correlation with transcriptome alterations. Conclusions We show that the panel is a good model for assessing the genetic basis of phenotypic heterogeneity and for providing insights into possible underlying molecular mechanisms. Our results reveal a high diversity and complexity underlying quantitative and qualitative transcriptional differences. PMID:22541052

  11. High Frequency of Pathogenic Rearrangements in SPG11 and Extensive Contribution of Mutational Hotspots and Founder Alleles.

    PubMed

    Günther, Sven; Elert-Dobkowska, Ewelina; Soehn, Anne S; Hinreiner, Sophie; Yoon, Grace; Heller, Raoul; Hellenbroich, Yorck; Hübner, Christian A; Ray, Peter N; Hehr, Ute; Bauer, Peter; Sulek, Anna; Beetz, Christian

    2016-07-01

    Biallelic loss-of-function mutations in SPG11 cause a wide spectrum of recessively inherited, neurodegenerative disorders including hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease. By comprehensive screening of three large cohorts of HSP index patients, we identified 83 alleles with "small" mutations and 13 alleles that carry large genomic rearrangements. Including relevant data from previous studies, we estimate that copy number variants (CNVs) account for ∼19% of pathogenic SPG11 alleles. The breakpoints for all novel and some previously reported CNVs were determined by long-range PCR and sequencing. This revealed several Alu-associated recombination hotspots. We also found evidence for additional mutational mechanisms, including for a two-step event in which an Alu retrotransposition preceded the actual rearrangement. Apparently independent samples with identical breakpoints were analyzed by microsatellite PCRs. The resulting haplotypes suggested the existence of two rearrangement founder alleles. Our findings widen the spectra of mutations and mutational mechanisms in SPG11, underscore the pivotal role played by Alus, and are of high diagnostic relevance for a wide spectrum of clinical phenotypes including the most frequent form of recessive HSP. PMID:27071356

  12. Genetic consequences of a century of protection: serial founder events and survival of the little spotted kiwi (Apteryx owenii)

    PubMed Central

    Ramstad, Kristina M.; Colbourne, Rogan M.; Robertson, Hugh A.; Allendorf, Fred W.; Daugherty, Charles H.

    2013-01-01

    We present the outcome of a century of post-bottleneck isolation of a long-lived species, the little spotted kiwi (Apteryx owenii, LSK) and demonstrate that profound genetic consequences can result from protecting few individuals in isolation. LSK were saved from extinction by translocation of five birds from South Island, New Zealand to Kapiti Island 100 years ago. The Kapiti population now numbers some 1200 birds and provides founders for new populations. We used 15 microsatellite loci to compare genetic variation among Kapiti LSK and the populations of Red Mercury, Tiritiri Matangi and Long Islands that were founded with birds from Kapiti. Two LSK native to D'Urville Island were also placed on Long Island. We found extremely low genetic variation and signatures of acute and recent genetic bottleneck effects in all four populations, indicating that LSK have survived multiple genetic bottlenecks. The Long Island population appears to have arisen from a single mating pair from Kapiti, suggesting there is no genetic contribution from D'Urville birds among extant LSK. The Ne/NC ratio of Kapiti Island LSK (0.03) is exceptionally low for terrestrial vertebrates and suggests that genetic diversity might still be eroding in this population, despite its large census size. PMID:23677342

  13. International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation.

    PubMed

    Peixoto, Ana; Santos, Catarina; Pinheiro, Manuela; Pinto, Pedro; Soares, Maria José; Rocha, Patrícia; Gusmão, Leonor; Amorim, António; van der Hout, Annemarie; Gerdes, Anne-Marie; Thomassen, Mads; Kruse, Torben A; Cruger, Dorthe; Sunde, Lone; Bignon, Yves-Jean; Uhrhammer, Nancy; Cornil, Lucie; Rouleau, Etienne; Lidereau, Rosette; Yannoukakos, Drakoulis; Pertesi, Maroulio; Narod, Steven; Royer, Robert; Costa, Maurício M; Lazaro, Conxi; Feliubadaló, Lidia; Graña, Begoña; Blanco, Ignacio; de la Hoya, Miguel; Caldés, Trinidad; Maillet, Philippe; Benais-Pont, Gaelle; Pardo, Bruno; Laitman, Yael; Friedman, Eitan; Velasco, Eladio A; Durán, Mercedes; Miramar, Maria-Dolores; Valle, Ana Rodriguez; Calvo, María-Teresa; Vega, Ana; Blanco, Ana; Diez, Orland; Gutiérrez-Enríquez, Sara; Balmaña, Judith; Ramon y Cajal, Teresa; Alonso, Carmen; Baiget, Montserrat; Foulkes, William; Tischkowitz, Marc; Kyle, Rachel; Sabbaghian, Nelly; Ashton-Prolla, Patricia; Ewald, Ingrid P; Rajkumar, Thangarajan; Mota-Vieira, Luisa; Giannini, Giuseppe; Gulino, Alberto; Achatz, Maria I; Carraro, Dirce M; de Paillerets, Brigitte Bressac; Remenieras, Audrey; Benson, Cindy; Casadei, Silvia; King, Mary-Claire; Teugels, Erik; Teixeira, Manuel R

    2011-06-01

    The c.156_157insAlu BRCA2 mutation has so far only been reported in hereditary breast/ovarian cancer (HBOC) families of Portuguese origin. Since this mutation is not detectable using the commonly used screening methodologies and must be specifically sought, we screened for this rearrangement in a total of 5,443 suspected HBOC families from several countries. Whereas the c.156_157insAlu BRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four individuals requesting predictive testing living in France and in the USA, all being Portuguese immigrants. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation occurred 558 ± 215 years ago. We further demonstrate significant quantitative differences regarding the production of the BRCA2 full length RNA and the transcript lacking exon 3 in c.156_157insAlu BRCA2 mutation carriers and in controls. The cumulative incidence of breast cancer in carriers did not differ from that of other BRCA2 and BRCA1 pathogenic mutations. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry are specifically tested for this rearrangement. PMID:20652400

  14. [Epidemiological and molecular study of autosomal dominant polycystic kidney disease (ADPKD) in the province of Vicenza, Italy: possible founder effect?].

    PubMed

    Corradi, Valentina; Gastaldon, Fiorella; Virzi', Grazia Maria; Clementi, Maurizio; Nalesso, Federico; Cruz, Dinna N; de Cal, Massimo; Torregrossa, Rossella; Ronco, Claudio

    2010-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disorder, with a prevalence of 1:400 to 1:1000. ADPKD is genetically and clinically heterogeneous. In addition, significant intrafamilial renal disease variability is evident. The prevalence of ADPKD patients on renal replacement therapy in Italy has been reported to be 8.2%. In the dialysis population of Vicenza province (northeast Italy), in one area especially, ADPKD cases account for 13.4%. We hypothesize that this high frequency is related to a founder effect in this geographically isolated population. Since April 2007 we have studied the characteristics of ADPKD patients and the presence of haplotypes shared by several families. The clinical profile of patients in the Vicenza province is similar to that described in the literature but there is a high prevalence of ADPKD in several isolated areas. These areas are characterized by the presence of three distinct haplotypes, suggesting a strong lineage-specific gene. PMID:21132648

  15. History of settlement of villages from Central Tunisia by studying families sharing a common founder Glycogenosis type III mutation.

    PubMed

    Rhouma, Faten Ben; Messai, Habib; Hsouna, Sana; Halim, Nizar Ben; Cherif, Wafa; Fadhel, Sihem Ben; Tiar, Afaf; Nagara, Majdi; Azzouz, Hatem; Sfar, Mohamed-Tahar; Dridi, Marie-Françoise Ben; Tebib, Neji; Ayadi, Abdelkarim; Abdelhak, Sonia; Kefi, Rym

    2016-09-01

    Glycogen storage disease type III (GSD III; Cori disease; Forbes disease) is an autosomal recessive inherited metabolic disorder resulting from deficient glycogen debrancher enzyme activity in liver and muscle. In this study, we focused on a single AGL gene mutation p.W1327X in 16 Tunisian patients from rural area surrounding the region of Mahdia in Central Tunisia. This constitutes the largest pool of patients with this mutation ever described. This study was performed to trace the history of the patients' ancestries in a single region. After extraction of genomic DNA, exon 31 of AGL gene was sequenced. The patients were investigated for the hypervariable segment 1 of mitochondrial DNA and 17 Y-STR markers. We found that the p.W1327X mutation was a founder mutation in Tunisia Analysis of maternal lineages shows an admixture of autochthonous North African, sub-Saharan and a predominance of Eurasian haplogroups. Heterogeneity of maternal haplogroups indicates an ancient settlement. However, paternal gene flow was highly homogeneous and originates from the Near East. We hypothesize that the p.W1327X mutation was introduced into the Tunisian population probably by a recent migration event; then the mutation was fixed in a small region due to the high rate of consanguineous marriages and genetic drift. The screening for this mutation should be performed in priority for GSD III molecular diagnosis, for patients from the region of Mahdia and those from regions sharing the same settlement history. PMID:26704523

  16. A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites

    PubMed Central

    Chong, Jessica X; Oktay, A Afşin; Dai, Zunyan; Swoboda, Kathryn J; Prior, Thomas W; Ober, Carole

    2011-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive (AR) neuromuscular disease that is one of the most common lethal genetic disorders in children, with carrier frequencies as high as ∼1 in 35 in US Whites. As part of our genetic studies in the Hutterites from South Dakota, we identified a large 22 Mb run of homozygosity, spanning the SMA locus in an affected child, of which 10 Mb was also homozygous in three affected Hutterites from Montana, supporting a single founder origin for the mutation. We developed a haplotype-based method for identifying carriers of the SMN1 deletion that leveraged existing genome-wide SNP genotype data for ∼1400 Hutterites. In combination with two direct PCR-based assays, we identified 176 carriers of the SMN1 deletion, one asymptomatic homozygous adult and three carriers of a de novo deletion. This corresponds to a carrier frequency of one in eight (12.5%) in the South Dakota Hutterites, representing the highest carrier frequency reported to date for SMA and for an AR disease in the Hutterite population. Lastly, we show that 26 SNPs can be used to predict SMA carrier status in the Hutterites, with 99.86% specificity and 99.71% sensitivity. PMID:21610747

  17. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations.

    PubMed

    Kachergus, Jennifer; Mata, Ignacio F; Hulihan, Mary; Taylor, Julie P; Lincoln, Sarah; Aasly, Jan; Gibson, J Mark; Ross, Owen A; Lynch, Timothy; Wiley, Joseph; Payami, Haydeh; Nutt, John; Maraganore, Demetrius M; Czyzewski, Krzysztof; Styczynska, Maria; Wszolek, Zbigniew K; Farrer, Matthew J; Toft, Mathias

    2005-04-01

    Autosomal dominant parkinsonism has been attributed to pathogenic amino acid substitutions in leucine-rich repeat kinase 2 (LRRK2). By sequencing multiplex families consistent with a PARK8 assignment, we identified a novel heterozygous LRRK2 mutation. A referral sample of 248 affected probands from families with autosomal dominant parkinsonism was subsequently assessed; 7 (2.8%) were found to carry a heterozygous LRRK2 6055G-->A transition (G2019S). These seven patients originate from the United States, Norway, Ireland, and Poland. In samples of patients with idiopathic Parkinson disease (PD) from the same populations, further screening identified six more patients with LRRK2 G2019S; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 have an LRRK2 G2019S substitution, 7 with a diagnosis of PD. Of note, all patients share an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years. In summary, our study demonstrates that LRRK2 G2019S accounts for parkinsonism in several families within Europe and North America. Our work highlights the fact that a proportion of clinically typical, late-onset PD cases have a genetic basis. PMID:15726496

  18. Rectal Transmission of Transmitted/Founder HIV-1 Is Efficiently Prevented by Topical 1% Tenofovir in BLT Humanized Mice

    PubMed Central

    Chateau, Morgan L.; Denton, Paul W.; Swanson, Michael D.; McGowan, Ian; Garcia, J. Victor

    2013-01-01

    Rectal microbicides are being developed to prevent new HIV infections in both men and women. We focused our in vivo preclinical efficacy study on rectally-applied tenofovir. BLT humanized mice (n = 43) were rectally inoculated with either the primary isolate HIV-1JRCSF or the MSM-derived transmitted/founder (T/F) virus HIV-1THRO within 30 minutes following treatment with topical 1% tenofovir or vehicle. Under our experimental conditions, in the absence of drug treatment we observed 50% and 60% rectal transmission by HIV-1JRCSF and HIV-1THRO, respectively. Topical tenofovir reduced rectal transmission to 8% (1/12; log rank p = 0.03) for HIV-1JRCSF and 0% (0/6; log rank p = 0.02) for HIV-1THRO. This is the first demonstration that any human T/F HIV-1 rectally infects humanized mice and that transmission of the T/F virus can be efficiently blocked by rectally applied 1% tenofovir. These results obtained in BLT mice, along with recent ex vivo, Phase 1 trial and non-human primate reports, provide a critically important step forward in the development of tenofovir-based rectal microbicides. PMID:23527295

  19. Genetic variation of the Turnip mosaic virus population of Vietnam: a case study of founder, regional and local influences.

    PubMed

    Nguyen, Huy Duc; Tran, Hoa Thi Nhu; Ohshima, Kazusato

    2013-01-01

    Turnip mosaic virus (TuMV) is one of the most important viruses infecting a wide range of plant species, primarily from the family Brassicaceae. Thirty TuMV isolates were collected from Brassica and Raphanus plants in Vietnam during 2006-2008. Host reaction studies showed that many of the isolates belonged to Brassica/Raphanus (BR) host-infecting type. Sequence-based phylogenetic and population genetic analyses were made of the complete polyprotein gene sequences, and of four non-recombinogenic regions of those sequences (i.e. genes of the helper-component proteinase protein, protein 3, nuclear inclusion b protein and coat protein). These were used to assess the subpopulation differentiation and divergence between Vietnamese TuMV populations and those of nearby Asian countries. Nine inter- and intralineage recombination type patterns were identified in the genomes of the Vietnamese isolates, of which seven were novel. All the Vietnamese non-recombinant isolates fell into the world-B group of TuMV and clustered with Chinese isolates. The estimates of genetic differentiation and gene flow reveal that the TuMV populations of Vietnam, China and Japan are genetically linked but have clear local founder effects. This, the first population genetic study of a TuMV population in Southeast Asia, indicates the importance of such studies for providing the scientific basis of control strategies. PMID:23201192

  20. A founder effect for p47(phox)Trp193Ter chronic granulomatous disease in Kavkazi Jews.

    PubMed

    de Boer, Martin; Tzur, Shay; van Leeuwen, Karin; Dencher, Paula C D; Skorecki, Karl; Wolach, Baruch; Gavrieli, Ronit; Nasidze, Ivane; Stoneking, Mark; Tanck, Michael W T; Roos, Dirk

    2015-12-01

    Chronic granulomatous disease (CGD) is a rare congenital immune deficiency caused by mutations in any of the five genes encoding NADPH oxidase subunits. One of these genes is NCF1, encoding the p47(phox) protein. A group of 39 patients, 14 of whom are of Kavkazi Jewish descent, was investigated for a founder effect for the mutation c.579G>A (p.Trp193Ter) in NCF1. We analyzed various genetic markers in the NCF1 region, including two single nucleotide polymorphisms (SNPs) in NCF1 and two short tandem repeats (STRs) located near NCF1. Most patients were homozygous for the c.579G>A mutation, but three patients were hemizygotes, with a deletion of NCF1 on the other allele, and three patients were compound heterozygotes with another mutation in NCF1. All Kavkazi Jewish patients had a c.295G_c.345T SNP combination in NCF1 and shared a common number of repeats in STR3. In addition, 90% of the Kavkazi Jewish patients shared a common number of repeats in STR1. This uniformity indicates that the c.579G>A mutation in NCF1 was introduced some 1200-2300 years ago in the Kavkazi Jewish population. Variation amongst the other investigated populations from the Middle East indicates that this mutation exists in these non-Kavkazi populations already for more than 5000 years. PMID:26460255

  1. Localization of the familial Mediterranean fever gene (FMF) to a 250-kb interval in non-Ashkenazi Jewish founder haplotypes

    SciTech Connect

    1996-09-01

    Chromosome 16p13.3 harbors a gene (MEF) associated with familial Mediterranean fever (FMF), a recessive disease very common in populations of Mediterranean ancestry. In the course of positional cloning of MEF, we genotyped 26 non-Ashkenazi Jewish FMF pedigrees (310 meioses) with 15 microsatellite markers, most of which were recently developed by Genethon. Identification of recombination events in the haplotypes allowed narrowing of the MEF interval to a region between D16S3124 (telomeric) and D16S475 (centromeric). Two markers, D16S3070 and D16S3275, a microsatellite marker isolated from a YAC that also contains D16S3070, showed no recombination with the disease. Linkage disequilibrium and haplotype analysis high-lighted the existence of a founder haplotype in our population. The core ancestral alleles were present in 71% of MEF-bearing chromosomes at loci D16S3070 and D16S3275. Furthermore, identification of historical crossing-over events in these pedigrees indicated that MEF is located between these two loci, which are both contained in a 250-kb genomic fragment. 24 refs., 4 figs., 3 tabs.

  2. Haplotype analysis and age estimation of the 113insR CDKN2A founder mutation in Swedish melanoma families.

    PubMed

    Hashemi, J; Bendahl, P O; Sandberg, T; Platz, A; Linder, S; Stierner, U; Olsson, H; Ingvar, C; Hansson, J; Borg, A

    2001-06-01

    Germline mutations in the CDKN2A tumor suppressor gene located on 9p21 have been linked to development of melanomas in some families. A germline 3-bp insertion in exon 2 of CDKN2A, leading to an extra arginine at codon 113 (113insR), has been identified in 17 Swedish melanoma families. Analysis of 10 microsatellite markers, spanning approximately 1 Mbp in the 9p21 region, showed that all families share a common allele for at least one of the markers closest to the CDKN2A gene, suggesting that the 113insR mutation is an ancestral founder mutation. Differences in the segregating haplotypes, due to meiotic recombinations and/or mutations in the short-tandem-repeat markers, were analyzed further to estimate the age of the mutation. Statistical analysis using a maximum likelihood approach indicated that the mutation arose 98 generations (90% confidence interval: 52-167 generations), or approximately 2,000 years, ago. Thus, 113insR would be expected to have a more widespread geographic distribution in European and North American regions with ancestral connections to Sweden. Alternatively, CDKN2A may lie in a recombination hot spot region, as suggested by the many meiotic recombinations in this narrow approximately 1-cM region on 9p21. PMID:11319798

  3. A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population.

    PubMed

    Webb, B D; Brandt, T; Liu, L; Jalas, C; Liao, J; Fedick, A; Linderman, M D; Diaz, G A; Kornreich, R; Trachtman, H; Mehta, L; Edelmann, L

    2014-08-01

    Alport syndrome is an inherited progressive nephropathy arising from mutations in the type IV collagen genes, COL4A3, COL4A4, and COL4A5. Symptoms also include sensorineural hearing loss and ocular lesions. We determined the molecular basis of Alport syndrome in a non-consanguineous Ashkenazi Jewish family with multiple affected females using linkage analysis and next generation sequencing. We identified a homozygous COL4A3 mutation, c.40_63del, in affected individuals with mutant alleles inherited from each parent on partially conserved haplotypes. Large-scale population screening of 2017 unrelated Ashkenazi Jewish samples revealed a carrier frequency of 1 in 183 indicating that COL4A3 c.40_63del is a founder mutation which may be a common cause of Alport syndrome in this population. Additionally, we determined that heterozygous mutation carriers in this family do not meet criteria for a diagnosis of Thin Basement Membrane Nephropathy and concluded that carriers of c.40_63del are not likely to develop benign familial hematuria. PMID:23927549

  4. The Role of bZIP Transcription Factors in Green Plant Evolution: Adaptive Features Emerging from Four Founder Genes

    PubMed Central

    Schrago, Carlos Guerra; dos Santos, Renato Vicentini; Mueller-Roeber, Bernd; Vincentz, Michel

    2008-01-01

    Background Transcription factors of the basic leucine zipper (bZIP) family control important processes in all eukaryotes. In plants, bZIPs are regulators of many central developmental and physiological processes including photomorphogenesis, leaf and seed formation, energy homeostasis, and abiotic and biotic stress responses. Here we performed a comprehensive phylogenetic analysis of bZIP genes from algae, mosses, ferns, gymnosperms and angiosperms. Methodology/Principal Findings We identified 13 groups of bZIP homologues in angiosperms, three more than known before, that represent 34 Possible Groups of Orthologues (PoGOs). The 34 PoGOs may correspond to the complete set of ancestral angiosperm bZIP genes that participated in the diversification of flowering plants. Homologous genes dedicated to seed-related processes and ABA-mediated stress responses originated in the common ancestor of seed plants, and three groups of homologues emerged in the angiosperm lineage, of which one group plays a role in optimizing the use of energy. Conclusions/Significance Our data suggest that the ancestor of green plants possessed four bZIP genes functionally involved in oxidative stress and unfolded protein responses that are bZIP-mediated processes in all eukaryotes, but also in light-dependent regulations. The four founder genes amplified and diverged significantly, generating traits that benefited the colonization of new environments. PMID:18698409

  5. Alfred Russel Wallace (1823-1913): the forgotten co-founder of the Neo-Darwinian theory of biological evolution.

    PubMed

    Kutschera, Ulrich; Hossfeld, Uwe

    2013-12-01

    The British naturalist Alfred Russel Wallace (1823-1913), who had to leave school aged 14 and never attended university, did extensive fieldwork, first in the Amazon River basin (1848-1852) and then in Southeast Asia (1854-1862). Based on this experience, and after reading the corresponding scientific literature, Wallace postulated that species were not created, but are modified descendants of pre-existing varieties (Sarawak Law paper, 1855). Evolution is brought about by a struggle for existence via natural selection, which results in the adaptation of those individuals in variable populations who survive and reproduce (Ternate essay, 1858). In his monograph Darwinism (1889), and in subsequent publications, Wallace extended the contents of Darwin's Origin of Species (1859) into the Neo-Darwinian theory of biological evolution, with reference to the work of August Weismann (1834-1914). Wallace also became the (co)-founder of biogeography, biodiversity research, astrobiology and evolutionary anthropology. Moreover, he envisioned what was later called the anthropocene (i.e., the age of human environmental destructiveness). However, since Wallace believed in atheistic spiritualism and mixed up scientific facts and supernatural speculations in some of his writings, he remains a controversial figure in the history of biology. PMID:23982797

  6. History of the ISS/SIC: Antoine Depage, one of the founders of the ISS/SIC.

    PubMed

    Van Hee, R

    2002-10-01

    Antoine Depage, born near Brussels in 1862, was one of the founders and first Secretary General of the Société Internationale de Chirurgie (ISS-SIC). After an excellent medical education at the Free Brussels University, he became professor at the same university at the age of 27. Surgically trained by Prof. Thiriar, he became one of the leading Belgian surgeons at the end of the nineteenth century, and he published more than 100 articles in national and international journals. In 1907 he founded a school for nurses in Brussels, to be directed by Edith Cavell. He also vigorously transformed the organization of the public hospitals in the Belgian capital. During World War I Queen Elisabeth appointed him surgeon-in-chief of the Océan-hospital in De Panne, where more than 50,000 soldiers with wounds, fractures, cerebral trauma, nitrous gas intoxication, and infectious diseases, among other problems were treated. The results he and his team obtained were excellent, and mortality was low. Many surgeons, including Alexis Carrel, as well as distinguished political leaders came to visit him in the hospital barracks. After the war he was honored by many political and scientific organizations, including the Société Internationale de Chirurgie. He served our Society not only as Secretary General from 1902 to 1912 but became President of the 4th Congress of the ISS-SIC in New York. Antoine Depage died after a long illness in 1925. PMID:12205562

  7. Puerto Rican founder mutation G787A in the SGCG gene: a case report of 2 siblings with LGMD 2C.

    PubMed

    DiCapua, Daniel; Patwa, Huned

    2014-03-01

    We describe 2 siblings who are homozygous for the G787A mutation in the γ-sarcoglycan gene (SGCG), who presented with a severe childhood onset limb-girdle muscular dystrophy, and share a similar clinical phenotype and disease course consistent with LGMD 2C. The siblings' mother is asymptomatic and is heterozygous for the same mutation. The father is estranged but presumably was also an asymptomatic heterozygous carrier as the father's sister (siblings' aunt) died of complications related to a muscular dystrophy at the age of 14. The paternal grandparents of these siblings were first cousins. All members of the family are of Puerto Rican ancestry supporting the theory that this is a founder mutation, as has been previously suggested by Duncan et al The clinical presentation, workup, and course of our patients are described in detail. These 2 cases effectively double the reported cases of this founder mutation. PMID:24534832

  8. Evidence for a founder effect of the germline fumarate hydratase gene mutation R58P causing hereditary leiomyomatosis and renal cell cancer (HLRCC).

    PubMed

    Heinritz, W; Paasch, U; Sticherling, M; Wittekind, C; Simon, J C; Froster, U G; Renner, R

    2008-01-01

    We report on the results of clinical investigation, pedigree analysis, mutation screening and haplotyping in a family with the syndrome of multiple cutaneous and uterine leiomyomas (MCUL1) and a germline missense mutation (R58P) in the fumarate hydratase gene (FH). We provide evidence for a founder effect for the identified mutation and distant relationship of our family to another familial case of MCUL1 associated with renal cell cancer, which was recently published with the same mutation. PMID:17908262

  9. A slowly progressive form of limb-girdle muscular dystrophy type 2C associated with founder mutation in the SGCG gene in Puerto Rican Hispanics

    PubMed Central

    Al-Zaidy, Samiah A; Malik, Vinod; Kneile, Kelley; Rosales, Xiomara Q; Gomez, Ana Maria; Lewis, Sarah; Hashimoto, Sayaka; Gastier-Foster, Julie; Kang, Peter; Darras, Basil; Kunkel, Louis; Carlo, Jose; Sahenk, Zarife; Moore, Steven A; Pyatt, Robert; Mendell, Jerry R

    2015-01-01

    Limb-girdle muscular dystrophy type 2C (LGMD2C) is considered one of the severe forms of childhood-onset muscular dystrophy. The geographical distribution of founder mutations in the SGCG gene has a prominent effect on the prevalence of LGMD2C in certain populations. The aim of this study was to confirm the hypothesis that the c.787G>A (p.E263K) mutation in the SGCG gene is a founder mutation among Puerto Rican Hispanics and to characterize the associated clinical and immunohistochemical phenotype. Genotyping of six polymorphic microsatellite markers internal to (D13S232) and flanking (D13S175, D13S292, D13S787, D13S1243, D13S283) the SGCG gene was performed on four unrelated Puerto Rican patients with LGMD2C. Preserved ambulation to the second decade of life was observed in at least two subjects. Immunostaining of skeletal muscle demonstrated absence of γ-sarcoglycan in all affected subjects. Two markers, D13S232 and D13S292, were highly informative and confirmed that all four families share the haplotype of the mutant allele. Our findings confirm that the E263K missense mutation in the SGCG gene is a founder mutation in Puerto Rican Hispanics. A slowly progressive disease course with prolonged preservation of ambulation can be seen in association with this mutation, providing evidence for phenotypic variability. PMID:25802879

  10. Identification of Genetic Variation on the Horse Y Chromosome and the Tracing of Male Founder Lineages in Modern Breeds

    PubMed Central

    Wallner, Barbara; Vogl, Claus; Shukla, Priyank; Burgstaller, Joerg P.; Druml, Thomas; Brem, Gottfried

    2013-01-01

    The paternally inherited Y chromosome displays the population genetic history of males. While modern domestic horses (Equus caballus) exhibit abundant diversity within maternally inherited mitochondrial DNA, no significant Y-chromosomal sequence diversity has been detected. We used high throughput sequencing technology to identify the first polymorphic Y-chromosomal markers useful for tracing paternal lines. The nucleotide variability of the modern horse Y chromosome is extremely low, resulting in six haplotypes (HT), all clearly distinct from the Przewalski horse (E. przewalskii). The most widespread HT1 is ancestral and the other five haplotypes apparently arose on the background of HT1 by mutation or gene conversion after domestication. Two haplotypes (HT2 and HT3) are widely distributed at high frequencies among modern European horse breeds. Using pedigree information, we trace the distribution of Y-haplotype diversity to particular founders. The mutation leading to HT3 occurred in the germline of the famous English Thoroughbred stallion “Eclipse” or his son or grandson and its prevalence demonstrates the influence of this popular paternal line on modern sport horse breeds. The pervasive introgression of Thoroughbred stallions during the last 200 years to refine autochthonous breeds has strongly affected the distribution of Y-chromosomal variation in modern horse breeds and has led to the replacement of autochthonous Y chromosomes. Only a few northern European breeds bear unique variants at high frequencies or fixed within but not shared among breeds. Our Y-chromosomal data complement the well established mtDNA lineages and document the male side of the genetic history of modern horse breeds and breeding practices. PMID:23573227

  11. Transmitted/Founder and Chronic HIV-1 Envelope Proteins Are Distinguished by Differential Utilization of CCR5

    PubMed Central

    Parker, Zahra F.; Iyer, Shilpa S.; Wilen, Craig B.; Parrish, Nicholas F.; Chikere, Kelechi C.; Lee, Fang-Hua; Didigu, Chuka A.; Berro, Reem; Klasse, Per Johan; Lee, Benhur; Moore, John P.; Shaw, George M.

    2013-01-01

    Infection by HIV-1 most often results from the successful transmission and propagation of a single virus variant, termed the transmitted/founder (T/F) virus. Here, we compared the attachment and entry properties of envelope (Env) glycoproteins from T/F and chronic control (CC) viruses. Using a panel of 40 T/F and 47 CC Envs, all derived by single genome amplification, we found that 52% of clade C and B CC Envs exhibited partial resistance to the CCR5 antagonist maraviroc (MVC) on cells expressing high levels of CCR5, while only 15% of T/F Envs exhibited this same property. Moreover, subtle differences in the magnitude with which MVC inhibited infection on cells expressing low levels of CCR5, including primary CD4+ T cells, were highly predictive of MVC resistance when CCR5 expression levels were high. These results are consistent with previous observations showing a greater sensitivity of T/F Envs to MVC inhibition on cells expressing very high levels of CCR5 and indicate that CC Envs are often capable of recognizing MVC-bound CCR5, albeit inefficiently on cells expressing physiologic levels of CCR5. When CCR5 expression levels are high, this phenotype becomes readily detectable. The utilization of drug-bound CCR5 conformations by many CC Envs was seen with other CCR5 antagonists, with replication-competent viruses, and did not obviously correlate with other phenotypic traits. The striking ability of clade C and B CC Envs to use MVC-bound CCR5 relative to T/F Envs argues that the more promiscuous use of CCR5 by these Env proteins is selected against at the level of virus transmission and is selected for during chronic infection. PMID:23269796

  12. Werner Ernst Reichardt Ph.D: founder of modern computational visual neurophysiology and anti-Nazi resistance fighter.

    PubMed

    Flynn, J T

    1999-01-01

    Werner Ernst Reichardt was born on January 30, 1924 in Berlin and at age 19 was drafted into the Luftwaffe and assigned to an electronic signals section laboratory. He became an active member of a resistance group and supplied radios for the movement in Germany. He emerged from the ashes of the Second World War and dedicated his scientific life to the development of the newborn specialty of biological physics. Following graduation from the Technische Hochschule Charlottenburg, he did a fellowship at CalTech under Max Delbrück. On returning to Germany he joined the Max Planck Institut and later became Director of the Max Planck Institut für Biologische Kybernetik in Tübingen, West Germany. Reichardt was one of the founders of the quantitative study of visually controlled orientation in animals. His work is very nearly unique in its close dialectic between elegant non-linear mathematical theory and quantitative experimental test of their predictions. During the 1950s Reichardt and his collaborators jointly developed an autocorrelation model (i.e. the firing rate of the involved visual neurones is closely correlated with the features of the pattern stimulating them) of how moving patterns are perceived by motion detectors in the visual system of the fly. This was the first mathematical description of a biological abstraction process. His findings apply to vertebrate vision, including motion detection and figure-ground description in human vision. His Max Planck Institute became a world renowned center for the computational approach to information processing by the nervous system. At his retirement party from the Institute he founded, Reichardt died on the evening of September 11th, 1992. PMID:11108122

  13. Genetic linkage mapping and transmission ratio distortion in a three-generation four-founder population of Panicum virgatum (L.).

    PubMed

    Li, Guifen; Serba, Desalegn D; Saha, Malay C; Bouton, Joseph H; Lanzatella, Christina L; Tobias, Christian M

    2014-05-01

    Switchgrass (Panicum virgatum L.), a warm season, C4, perennial grass, is one of the predominant grass species of the North American tall grass prairies. It is viewed as a high-potential bioenergy feedstock species because it can produce large amounts of lignocellulosic material with relatively few inputs. The objectives of this project were to develop an advanced switchgrass population and use it for the construction of genetic linkage maps and trait characterization. A three-generation, four-founder population was created and a total of 182 progeny of this advanced population were genotyped, including a mixture of self-pollinated and hybrid individuals. The female map integrated both subpopulations and covered 1629 cM of the switchgrass genome, with an average map length of 91 cM per linkage group. The male map of the hybrid progeny covered 1462 cM, with an average map length of 81 cM per linkage group. Average marker density of the female and male maps was 3.9 and 3.5 cM per marker interval, respectively. Based on the parental maps, the genome length of switchgrass was estimated to be 1776 cM and 1596 cM for the female map and male map, respectively. The proportion of the genome within 5 cM of a mapped locus was estimated to be 92% and 93% for the female map and male map, respectively. Thus, the linkage maps have covered most of the switchgrass genome. The assessment of marker transmission ratio distortion found that 26% of the genotyped markers were distorted from either 1:1 or 3:1 ratios expected for segregation of single dose markers in one or both parents, respectively. Several regions affected by transmission ratio distortion were found, with linkage groups Ib-m and VIIIa-f most affected. PMID:24637352

  14. Impact of immune escape mutations on HIV-1 fitness in the context of the cognate transmitted/founder genome

    PubMed Central

    2012-01-01

    Background A modest change in HIV-1 fitness can have a significant impact on viral quasispecies evolution and viral pathogenesis, transmission and disease progression. To determine the impact of immune escape mutations selected by cytotoxic T lymphocytes (CTL) on viral fitness in the context of the cognate transmitted/founder (T/F) genome, we developed a new competitive fitness assay using molecular clones of T/F genomes lacking exogenous genetic markers and a highly sensitive and precise parallel allele-specific sequencing (PASS) method. Results The T/F and mutant viruses were competed in CD4+ T-cell enriched cultures, relative proportions of viruses were assayed after repeated cell-free passage, and fitness costs were estimated by mathematical modeling. Naturally occurring HLA B57-restricted mutations involving the TW10 epitope in Gag and two epitopes in Tat/Rev and Env were assessed independently and together. Compensatory mutations which restored viral replication fitness were also assessed. A principal TW10 escape mutation, T242N, led to a 42% reduction in replication fitness but V247I and G248A mutations in the same epitope restored fitness to wild-type levels. No fitness difference was observed between the T/F and a naturally selected variant carrying the early CTL escape mutation (R355K) in Env and a reversion mutation in the Tat/Rev overlapping region. Conclusions These findings reveal a broad spectrum of fitness costs to CTL escape mutations in T/F viral genomes, similar to recent findings reported for neutralizing antibody escape mutations, and highlight the extraordinary plasticity and adaptive potential of the HIV-1 genome. Analysis of T/F genomes and their evolved progeny is a powerful approach for assessing the impact of composite mutational events on viral fitness. PMID:23110705

  15. Genetic Linkage Mapping and Transmission Ratio Distortion in a Three-Generation Four-Founder Population of Panicum virgatum (L.)

    PubMed Central

    Li, Guifen; Serba, Desalegn D.; Saha, Malay C.; Bouton, Joseph H.; Lanzatella, Christina L.; Tobias, Christian M.

    2014-01-01

    Switchgrass (Panicum virgatum L.), a warm season, C4, perennial grass, is one of the predominant grass species of the North American tall grass prairies. It is viewed as a high-potential bioenergy feedstock species because it can produce large amounts of lignocellulosic material with relatively few inputs. The objectives of this project were to develop an advanced switchgrass population and use it for the construction of genetic linkage maps and trait characterization. A three-generation, four-founder population was created and a total of 182 progeny of this advanced population were genotyped, including a mixture of self-pollinated and hybrid individuals. The female map integrated both subpopulations and covered 1629 cM of the switchgrass genome, with an average map length of 91 cM per linkage group. The male map of the hybrid progeny covered 1462 cM, with an average map length of 81 cM per linkage group. Average marker density of the female and male maps was 3.9 and 3.5 cM per marker interval, respectively. Based on the parental maps, the genome length of switchgrass was estimated to be 1776 cM and 1596 cM for the female map and male map, respectively. The proportion of the genome within 5 cM of a mapped locus was estimated to be 92% and 93% for the female map and male map, respectively. Thus, the linkage maps have covered most of the switchgrass genome. The assessment of marker transmission ratio distortion found that 26% of the genotyped markers were distorted from either 1:1 or 3:1 ratios expected for segregation of single dose markers in one or both parents, respectively. Several regions affected by transmission ratio distortion were found, with linkage groups Ib-m and VIIIa-f most affected. PMID:24637352

  16. Concordance of nuclear and mitochondrial DNA markers in detecting a founder event in Lake Clark sockeye salmon

    USGS Publications Warehouse

    Ramstad, Kristina M.; Woody, Carol Ann; Habicht, Chris; Sage, G. Kevin; Seeb, James E.; Allendorf, Fred W.

    2007-01-01

    Genetic bottleneck effects can reduce genetic variation, persistence probability, and evolutionary potential of populations. Previous microsatellite analysis suggested a bottleneck associated with a common founding of sock-eye salmon Oncorhynchus nerka populations of Lake Clark, Alaska, about 100 to 400 generations ago. The common foundingevent occurred after the last glacial recession and resulted in reduced allelic diversity and strong divergence of Lake Clarksockeye salmon relative to neighboring Six Mile Lake and LakeIliamna populations. Here we used two additional genetic marker types (allozymes and mtDNA) to examine these patterns further. Allozyme and mtDNA results were congruent with the microsatellite data in suggesting a common founder event in LakeClark sockeye salmon and confirmed the divergence of Lake Clarkpopulations from neighboring Six Mile Lake and Lake Iliamna populations. The use of multiple marker types provided better understanding of the bottleneck in Lake Clark. For example, the Sucker Bay Lake population had an exceptionally severe reduction in allelic diversity at microsatellite loci, but not at mtDNA. This suggests that the reduced microsatellite variation in Sucker Bay Lake fish is due to consistently smaller effective population size than other Lake Clark populations, rather than a more acute or additional bottleneck since founding. Caution is urged in using reduced heterozygosity as a measure of genetic bottleneck effects because stochastic variance among loci resulted in an overall increase in allozyme heterozygosity within bottlenecked Lake Clark populations. However, heterozygosity excess, which assesses heterozygosity relative to allelic variation, detected genetic bottleneck effects in both allozyme and microsatellite loci. 

  17. Primary open angle glaucoma due to T377M MYOC: Population mapping of a Greek founder mutation in Northwestern Greece

    PubMed Central

    Kitsos, George; Petrou, Zacharias; Grigoriadou, Maria; Samples, John R; Hewitt, Alex W; Kokotas, Haris; Giannoulia-Karantana, Aglaia; Mackey, David A; Wirtz, Mary K; Moschou, Marilita; Ioannidis, John PA; Petersen, Michael B

    2010-01-01

    Background: Mutations in the MYOC gene have been shown to explain 5% of unrelated primary open angle glaucoma (POAG) in different populations. In particular, the T377M MYOC mutation has arisen at least three separate times in history, in Great Britain, India, and Greece. The purpose of this study is to investigate the distribution of the mutation among different population groups in the northwestern region of Greece. Materials and methods: We explored the distribution of the “Greek” T377M founder mutation in the Epirus region in Northwestern Greece, which could be its origin. Genotyping was performed in POAG cases and controls by PCR amplification of the MYOC gene, followed by digestion with restriction enzyme. Statistical analyses were performed by an exact test, the Kaplan–Meier method and the t-test. Results: In the isolated Chrysovitsa village in the Pindus Mountains, a large POAG family demonstrated the T377M mutation in 20 of 66 family members while no controls from the Epirus region (n = 124) carried this mutation (P < 0.001). Among other POAG cases from Epirus, 2 out of 14 familial cases and 1 out of 80 sporadic cases showed the mutation (P = 0.057). The probability of POAG diagnosis with advancing age among mutation carriers was 23% at age 40, and reached 100% at age 75. POAG patients with the T377M mutation were diagnosed at a mean age of 51 years (SD ± 13.9), which is younger than the sporadic or familial POAG cases: 63.1 (SD ± 11) and 66.8 (SD ± 9.8) years, respectively. Conclusions: The T377M mutation was found in high proportion in members of the Chrysovitsa family (30.3%), in lower proportion in familial POAG cases (14.2%) and seems rare in sporadic POAG cases (1.2%), while no controls (0%) from the Epirus region carried the mutation. Historical and geographical data may explain the distribution of this mutation within Greece and worldwide. PMID:20390039

  18. Specific mutations in the HEXA gene among Iraqi Jewish Tay-Sachs disease carriers: dating of founder ancestor.

    PubMed

    Karpati, Mazal; Gazit, Ephraim; Goldman, Boleslaw; Frisch, Amos; Colombo, Roberto; Peleg, Leah

    2004-02-01

    The incidence of Tay-Sachs disease (TSD) carriers, as defined by enzyme assay, is 1:29 among Ashkenazi Jews and 1:110 among Moroccan Jews. An elevated carrier frequency of 1:140 was also observed in the Iraqi Jews (IJ), while in other Israeli populations the world's pan-ethnic frequency of approximately 1:280 has been found. Recently a novel mutation, G749T, has been reported in 38.7% of the IJ carriers (24/62). Here we report a second novel HEXA mutation specific to the IJ TDS carriers: a substitution of cytosine 1351 by guanosine (C1351G), resulting in the change of leucine to valine in position 451. This mutation was found in 33.9% (21/62) of the carriers and in none of 100 non-carrier IJ. In addition to the two specific mutations, 14.5% (9/62) of the IJ carriers bear a known "Jewish" mutation (Ashkenazi or Moroccan) and 11.3% (7/62) carry a known "non-Jewish" mutation. In 1 DNA sample no mutation has yet been detected. To investigate the genetic history of the IJ-specific mutations (C1351G and G749T), the allelic distribution of four polymorphic markers (D15S131, D15S1025, D15S981, D15S1050) was analyzed in IJ heterozygotes and ethnically matched controls. Based on linkage disequilibrium, recombination factor (theta) between the markers and mutated loci, and the population growth correction, we deduced that G749T occurred in a founder ancestor 44.8 +/- 14.2 generations (g) ago [95% confidence interval (CI) 17.0-72.6 g] and C1351G arose 80.4 +/- 35.9 g ago (95% CI 44.5-116.3 g). Thus, the estimated dates for introduction of mutations are: 626 +/- 426 A.D. (200-1052 A.D.) for G749T and 442 +/- 1077 B.C. (1519 B.C. to 635 A.D.) for C1351G. PMID:14648242

  19. The Founder Strains of the Collaborative Cross Express a Complex Combination of Advantageous and Deleterious Traits for Male Reproduction

    PubMed Central

    Odet, Fanny; Pan, Wenqi; Bell, Timothy A.; Goodson, Summer G.; Stevans, Alicia M.; Yun, Zianing; Aylor, David L.; Kao, Chia-Yu; McMillan, Leonard; de Villena, Fernando Pardo-Manuel; O’Brien, Deborah A.

    2015-01-01

    Surveys of inbred strains of mice are standard approaches to determine the heritability and range of phenotypic variation for biomedical traits. In addition, they may lead to the identification of novel phenotypes and models of human disease. Surprisingly, male reproductive phenotypes are among the least-represented traits in the Mouse Phenome Database. Here we report the results of a broad survey of the eight founder inbred strains of both the Collaborative Cross (CC) and the Diversity Outbred populations, two new mouse resources that are being used as platforms for systems genetics and sources of mouse models of human diseases. Our survey includes representatives of the three main subspecies of the house mice and a mix of classical and wild-derived inbred strains. In addition to standard staples of male reproductive phenotyping such as reproductive organ weights, sperm counts, and sperm morphology, our survey includes sperm motility and the first detailed survey of testis histology. As expected for such a broad survey, heritability varies widely among traits. We conclude that although all eight inbred strains are fertile, most display a mix of advantageous and deleterious male reproductive traits. The CAST/EiJ strain is an outlier, with an unusual combination of deleterious male reproductive traits including low sperm counts, high levels of morphologically abnormal sperm, and poor motility. In contrast, sperm from the PWK/PhJ and WSB/EiJ strains had the greatest percentages of normal morphology and vigorous motility. Finally, we report an abnormal testis phenotype that is highly heritable and restricted to the WSB/EiJ strain. This phenotype is characterized by the presence of a large, but variable, number of vacuoles in at least 10% of the seminiferous tubules. The onset of the phenotype between 2 and 3 wk of age is temporally correlated with the formation of the blood-testis barrier. We speculate that this phenotype may play a role in high rates of extinction in

  20. MSH2 c.1452–1455delAATG Is a Founder Mutation and an Important Cause of Hereditary Nonpolyposis Colorectal Cancer in the Southern Chinese Population

    PubMed Central

    Chan, Tsun Leung; Wai Chan, Yee; Ho, Judy W. C.; Chan, Celine; Chan, Annie S. Y.; Chan, Emily; Lam, Polly W. Y.; Wah Tse, Chun; Cheong Lee, Kam; Wai Lau, Chi; Gwi, Elaine; Yi Leung, Suet; Yuen, Siu Tsan

    2004-01-01

    Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for ∼2% of all colorectal cancer (CRC) cases and is the most common hereditary CRC syndrome. We have previously reported a high incidence of microsatellite instability (MSI) and germline mismatch repair (MMR) gene mutations in young Hong Kong Chinese with CRC. Ongoing studies at the Hereditary Gastrointestinal Cancer Registry in Hong Kong have revealed a unique germline MSH2 c.1452–1455delAATG mutation that has not been reported in other ethnic groups. Detailed analysis showed that this specific MSH2 mutation constituted 21% of all germline MMR gene mutations and 36% of all MSH2 germline mutations identified. We designed a specific PCR-based diagnostic test on paraffin-embedded tissues and identified this germline mutation in 2 (1.5%) of 138 consecutive patients with early-onset CRC (<46 years of age at diagnosis). Haplotype analysis was performed using 11 microsatellite markers located between D2S391 and D2S123. All 10 families had the same disease haplotype, suggesting a founder effect. These 10 families all originated from the Chinese province of Guangdong, which historically included Hong Kong. It is the most populous of the Chinese provinces, with a population of >93 million. Further analysis suggested that this founder mutation may date back to between 22 and 103 generations ago. The identification of this MSH2 founder mutation has important implications for the design of mutation-detection strategies for the southern Chinese population. Since there were major emigrations from Hong Kong and Guangdong province during the 19th and 20th centuries, this finding is also significant for Chinese communities worldwide. PMID:15042510

  1. Localization of the gene causing keratolytic winter erythema to chromosome 8p22-p23, and evidence for a founder effect in South African Afrikaans-speakers.

    PubMed Central

    Starfield, M; Hennies, H C; Jung, M; Jenkins, T; Wienker, T; Hull, P; Spurdle, A; Küster, W; Ramsay, M; Reis, A

    1997-01-01

    Keratolytic winter erythema (KWE), also known as "Oudtshoorn skin disease," or "erythrokeratolysis hiemalis," is an autosomal dominant skin disorder of unknown etiology characterized by a cyclical erythema, hyperkeratosis, and recurrent and intermittent peeling of the palms and soles, particularly during winter. Initially KWE was believed to be unique to South Africa, but recently a large pedigree of German origin has been identified. The disorder occurs with a prevalence of 1/7,000 in the South African Afrikaans-speaking Caucasoid population, and this high frequency has been attributed to founder effect. After a number of candidate regions were excluded from linkage to KWE in both the German family and several South African families, a genomewide analysis was embarked on. Linkage to the microsatellite marker D8S550 on chromosome 8p22-p23 was initially observed, with a maximum LOD score (Z(max)) of 9.2 at a maximum recombination fraction (theta(max)) of .0 in the German family. Linkage was also demonstrated in five of the larger South African families, with Z(max) = 7.4 at theta(max) = .02. When haplotypes were constructed, 11 of 14 South African KWE families had the complete "ancestral" haplotype, and 3 demonstrated conservation of parts of this haplotype, supporting the hypothesis of founder effect. The chromosome segregating with the disease in the German family demonstrated a different haplotype, suggesting that these chromosomes do not have a common origin. Recombination events place the KWE gene in a 6-cM interval between D8S550 and D8S552. If it is assumed that there was a single South African founder, a proposed ancestral recombinant suggests that the gene is most likely in a 1-cM interval between D8S550 and D8S265. PMID:9311742

  2. Prevalence of the BRCA1 founder mutation c.5266dupin Brazilian individuals at-risk for the hereditary breast and ovarian cancer syndrome

    PubMed Central

    2011-01-01

    About 5-10% of breast and ovarian carcinomas are hereditary and most of these result from germline mutations in the BRCA1 and BRCA2 genes. In women of Ashkenazi Jewish ascendance, up to 30% of breast and ovarian carcinomas may be attributable to mutations in these genes, where 3 founder mutations, c.68_69del (185delAG) and c.5266dup (5382insC) in BRCA1 and c.5946del (6174delT) in BRCA2, are commonly encountered. It has been suggested by some authors that screening for founder mutations should be undertaken in all Brazilian women with breast cancer. Thus, the goal of this study was to determine the prevalence of three founder mutations, commonly identified in Ashkenazi individuals in a sample of non-Ashkenazi cancer-affected Brazilian women with clearly defined risk factors for hereditary breast and ovarian cancer (HBOC) syndrome. Among 137 unrelated Brazilian women from HBOC families, the BRCA1c.5266dup mutation was identified in seven individuals (5%). This prevalence is similar to that encountered in non-Ashkenazi HBOC families in other populations. However, among patients with bilateral breast cancer, the frequency of c.5266dup was significantly higher when compared to patients with unilateral breast tumors (12.1% vs 1.2%, p = 0.023). The BRCA1 c.68_69del and BRCA2 c.5946del mutations did not occur in this sample. We conclude that screening non-Ashkenazi breast cancer-affected women from the ethnically heterogeneous Brazilian populations for the BRCA1 c.68_69del and BRCA2 c.5946del is not justified, and that screening for BRCA1c.5266dup should be considered in high risk patients, given its prevalence as a single mutation. In high-risk patients, a negative screening result should always be followed by comprehensive BRCA gene testing. The finding of a significantly higher frequency of BRCA1 c.5266dup in women with bilateral breast cancer, as well as existence of other as yet unidentified founder mutations in this population, should be further assessed in a larger

  3. The initial antibody response to HIV-1: induction of ineffective early B cell responses against GP41 by the transmitted/founder virus

    SciTech Connect

    Chavez, Leslie L; Perelson, Alan

    2008-01-01

    A window of opportunity for immune responses to extinguish HIV -1 exists from the moment of transmission through establishment of the latent pool of HIV -I-infected cells. A critical time to study the initial immune responses to the transmitted/founder virus is the eclipse phase of HIV-1 infection (time from transmission to the first appearance of plasma virus) but, to date, this period has been logistically difficult to analyze. Studies in non-human primates challenged with chimeric simianhuman immunodeficiency virus have shown that neutralizing antibodies, when present at the time of infection, can prevent virus infection.

  4. Striking intrafamilial phenotypic variability in Aicardi-Goutières syndrome associated with the recurrent Asian founder mutation in RNASEH2C.

    PubMed

    Vogt, Julie; Agrawal, Shakti; Ibrahim, Zala; Southwood, Taunton R; Philip, Sunny; Macpherson, Lesley; Bhole, Malini V; Crow, Yanick J; Oley, Christine

    2013-02-01

    Aicardi-Goutières syndrome (AGS) is an encephalopathy of early childhood which is most commonly inherited as an autosomal recessive trait. The disorder demonstrates significant genetic heterogeneity with causative mutations in five genes identified to date. Although most patients with AGS experience a severe neonatal or infantile presentation, poor neurodevelopmental outcome and reduced survival, clinical variability in the onset and severity of the condition is being increasingly recognized. A later presentation with a more variable effect on development, morbidity and mortality has been particularly observed in association with mutations in SAMHD1 and RNASEH2B. In contrast, the recurrent c.205C > T (p.R69W) RNASEH2C Asian founder mutation has previously only been identified in children with a severe AGS phenotype. Here, to our knowledge, we present the first report of marked phenotypic variability in siblings both harboring this founder mutation in the homozygous state. In this family, one female child had a severe AGS phenotype with an onset in infancy and profound developmental delay, whilst an older sister was of completely normal intellect with a normal head circumference and was only diagnosed because of the presence of chilblains and a mild hemiplegia. An appreciation of intrafamilial phenotypic expression is important in the counseling of families considering prenatal diagnosis, and may also be relevant to the assessment of efficacy in future clinical trials. In addition, marked phenotypic variation raises the possibility that more mildly affected patients are not currently identified. PMID:23322642

  5. Genetic Variability and Founder Effect in the Pitcher Plant Sarracenia purpurea (Sarraceniaceae) in Populations Introduced into Switzerland: from Inbreeding to Invasion

    PubMed Central

    PARISOD, CHRISTIAN; TRIPPI, CHARLOTTE; GALLAND, NICOLE

    2004-01-01

    • Background and Aims The long-lived and mainly outcrossing species Sarracenia purpurea has been introduced into Switzerland and become invasive. This creates the opportunity to study reactions to founder effect and how a species can circumvent deleterious effects of bottlenecks such as reduced genetic diversity, inbreeding and extinction through mutational meltdown, to emerge as a highly invasive plant. • Methods A population genetic survey by random amplified polymorphism DNA markers (RAPD) together with historical insights and a field pollination experiment were carried out. • Key Results At the regional scale, S. purpurea shows low structure (θst = 0·072) due to a recent founder event and important subsequent growth. Nevertheless, multivariate statistical analyses reveal that, because of a bottleneck that shifted allele frequencies, most of the variability is independent among populations. In one population (Tenasses) the species has become invasive and genetic analysis reveals restricted gene flow and family structure (θst = 0·287). Although inbreeding appears to be high (Fis > 0·410 from a Bayesian estimation), a field pollination experiment failed to detect significant inbreeding depression upon F1 seed number and seed weight fitness-traits. Furthermore, crosses between unrelated individuals produced F1 seeds with significantly reduced fitness, thus showing local outbreeding depression. • Conclusions The results suggest that, under restricted gene flow among families, the species may not only have rapidly purged deleterious alleles, but also have undergone some form of selection for inbreeding due to co-adaptation between loci. PMID:15546932

  6. Analysis of Founder Mutations in Rare Tumors Associated With Hereditary Breast/Ovarian Cancer Reveals a Novel Association of BRCA2 Mutations with Ampulla of Vater Carcinomas

    PubMed Central

    Pinto, Pedro; Peixoto, Ana; Santos, Catarina; Rocha, Patrícia; Pinto, Carla; Pinheiro, Manuela; Leça, Luís; Martins, Ana Teresa; Ferreira, Verónica; Bartosch, Carla

    2016-01-01

    BRCA1 and BRCA2 mutations are responsible for hereditary breast and ovarian cancer, but they also confer an increased risk for the development of rarer cancers associated with this syndrome, namely, cancer of the pancreas, male breast, peritoneum, and fallopian tube. The objective of this work was to quantify the contribution of the founder mutations BRCA2 c.156_157insAlu and BRCA1 c.3331_3334del for cancer etiology in unselected hospital-based cohorts of Portuguese patients diagnosed with these rarer cancers, by using a strategy that included testing of archival tumor tissue. A total of 102 male breast, 68 pancreatic and 33 peritoneal/fallopian tube carcinoma cases were included in the study. The BRCA2 c.156_157insAlu mutation was observed with a frequency of 7.8% in male breast cancers, 3.0% in peritoneal/fallopian tube cancers, and 1.6% in pancreatic cancers, with estimated total contributions of germline BRCA2 mutations of 14.3%, 5.5%, and 2.8%, respectively. No carriers of the BRCA1 c.3331_3334del mutation were identified. During our study, a patient with an ampulla of Vater carcinoma was incidentally found to carry the BRCA2 c.156_157insAlu mutation, so we decided to test a consecutive series of additional 15 ampullary carcinomas for BRCA1/BRCA2 mutations using a combination of direct founder mutation testing and full gene analysis with next generation sequencing. BRCA2 mutations were observed with a frequency of 14.3% in ampulla of Vater carcinomas. In conclusion, taking into account the implications for both the individuals and their family members, we recommend that patients with these neoplasias should be offered BRCA1/BRCA2 genetic testing and we here show that it is feasible to test for founder mutations in archival tumor tissue. Furthermore, we identified for the first time a high frequency of germline BRCA2 mutations in ampullary cancers. PMID:27532258

  7. Analysis of Founder Mutations in Rare Tumors Associated With Hereditary Breast/Ovarian Cancer Reveals a Novel Association of BRCA2 Mutations with Ampulla of Vater Carcinomas.

    PubMed

    Pinto, Pedro; Peixoto, Ana; Santos, Catarina; Rocha, Patrícia; Pinto, Carla; Pinheiro, Manuela; Leça, Luís; Martins, Ana Teresa; Ferreira, Verónica; Bartosch, Carla; Teixeira, Manuel R

    2016-01-01

    BRCA1 and BRCA2 mutations are responsible for hereditary breast and ovarian cancer, but they also confer an increased risk for the development of rarer cancers associated with this syndrome, namely, cancer of the pancreas, male breast, peritoneum, and fallopian tube. The objective of this work was to quantify the contribution of the founder mutations BRCA2 c.156_157insAlu and BRCA1 c.3331_3334del for cancer etiology in unselected hospital-based cohorts of Portuguese patients diagnosed with these rarer cancers, by using a strategy that included testing of archival tumor tissue. A total of 102 male breast, 68 pancreatic and 33 peritoneal/fallopian tube carcinoma cases were included in the study. The BRCA2 c.156_157insAlu mutation was observed with a frequency of 7.8% in male breast cancers, 3.0% in peritoneal/fallopian tube cancers, and 1.6% in pancreatic cancers, with estimated total contributions of germline BRCA2 mutations of 14.3%, 5.5%, and 2.8%, respectively. No carriers of the BRCA1 c.3331_3334del mutation were identified. During our study, a patient with an ampulla of Vater carcinoma was incidentally found to carry the BRCA2 c.156_157insAlu mutation, so we decided to test a consecutive series of additional 15 ampullary carcinomas for BRCA1/BRCA2 mutations using a combination of direct founder mutation testing and full gene analysis with next generation sequencing. BRCA2 mutations were observed with a frequency of 14.3% in ampulla of Vater carcinomas. In conclusion, taking into account the implications for both the individuals and their family members, we recommend that patients with these neoplasias should be offered BRCA1/BRCA2 genetic testing and we here show that it is feasible to test for founder mutations in archival tumor tissue. Furthermore, we identified for the first time a high frequency of germline BRCA2 mutations in ampullary cancers. PMID:27532258

  8. Identification of BRCA1/2 Founder Mutations in Southern Chinese Breast Cancer Patients Using Gene Sequencing and High Resolution DNA Melting Analysis

    PubMed Central

    Kwong, Ava; Ng, Enders Kai On; Wong, Chris Lei Po; Law, Fian Bic Fai; Au, Tommy; Wong, Hong Nei; Kurian, Allison W.; West, Dee W.; Ford, James M.; Ma, Edmond Siu Kwan

    2012-01-01

    Background Ethnic variations in breast cancer epidemiology and genetics have necessitated investigation of the spectra of BRCA1 and BRCA2 mutations in different populations. Knowledge of BRCA mutations in Chinese populations is still largely unknown. We conducted a multi-center study to characterize the spectra of BRCA mutations in Chinese breast and ovarian cancer patients from Southern China. Methodology/Principal Findings A total of 651 clinically high-risk breast and/or ovarian cancer patients were recruited from the Hong Kong Hereditary Breast Cancer Family Registry from 2007 to 2011. Comprehensive BRCA1 and BRCA2 mutation screening was performed using bi-directional sequencing of all coding exons of BRCA1 and BRCA2. Sequencing results were confirmed by in-house developed full high resolution DNA melting (HRM) analysis. Among the 451 probands analyzed, 69 (15.3%) deleterious BRCA mutations were identified, comprising 29 in BRCA1 and 40 in BRCA2. The four recurrent BRCA1 mutations (c.470_471delCT, c.3342_3345delAGAA, c.5406+1_5406+3delGTA and c.981_982delAT) accounted for 34.5% (10/29) of all BRCA1 mutations in this cohort. The four recurrent BRCA2 mutations (c.2808_2811delACAA, c.3109C>T, c.7436_7805del370 and c.9097_9098insA) accounted for 40% (16/40) of all BRCA2 mutations. Haplotype analysis was performed to confirm 1 BRCA1 and 3 BRCA2 mutations are putative founder mutations. Rapid HRM mutation screening for a panel of the founder mutations were developed and validated. Conclusion In this study, our findings suggest that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer in Southern Chinese population. Knowing the spectrum and frequency of the founder mutations in this population will assist in the development of a cost-effective rapid screening assay, which in turn facilitates genetic counseling and testing for the purpose of cancer risk assessment. PMID:22970155

  9. Sexually-Transmitted/Founder HIV-1 Cannot Be Directly Predicted from Plasma or PBMC-Derived Viral Quasispecies in the Transmitting Partner

    PubMed Central

    Frange, Pierre; Meyer, Laurence; Jung, Matthieu; Goujard, Cecile; Zucman, David; Abel, Sylvie; Hochedez, Patrick; Gousset, Marine; Gascuel, Olivier; Rouzioux, Christine; Chaix, Marie-Laure

    2013-01-01

    Objective Characterization of HIV-1 sequences in newly infected individuals is important for elucidating the mechanisms of viral sexual transmission. We report the identification of transmitted/founder viruses in eight pairs of HIV-1 sexually-infected patients enrolled at the time of primary infection (“recipients”) and their transmitting partners (“donors”). Methods Using a single genome-amplification approach, we compared quasispecies in donors and recipients on the basis of 316 and 376 C2V5 env sequences amplified from plasma viral RNA and PBMC-associated DNA, respectively. Results Both DNA and RNA sequences indicated very homogeneous viral populations in all recipients, suggesting transmission of a single variant, even in cases of recent sexually transmitted infections (STIs) in donors (n = 2) or recipients (n = 3). In all pairs, the transmitted/founder virus was derived from an infrequent variant population within the blood of the donor. The donor variant sequences most closely related to the recipient sequences were found in plasma samples in 3/8 cases and/or in PBMC samples in 6/8 cases. Although donors were exclusively (n = 4) or predominantly (n = 4) infected by CCR5-tropic (R5) strains, two recipients were infected with highly homogeneous CXCR4/dual-mixed-tropic (X4/DM) viral populations, identified in both DNA and RNA. The proportion of X4/DM quasispecies in donors was higher in cases of X4/DM than R5 HIV transmission (16.7–22.0% versus 0–2.6%), suggesting that X4/DM transmission may be associated with a threshold population of X4/DM circulating quasispecies in donors. Conclusions These suggest that a severe genetic bottleneck occurs during subtype B HIV-1 heterosexual and homosexual transmission. Sexually-transmitted/founder virus cannot be directly predicted by analysis of the donor’s quasispecies in plasma and/or PBMC. Additional studies are required to fully understand the traits that confer the capacity to transmit and

  10. Genetic variability, differentiation, and founder effect in golden jackals (Canis aureus) from Serbia as revealed by mitochondrial DNA and nuclear microsatellite loci.

    PubMed

    Zachos, Frank E; Cirovic, Dusko; Kirschning, Julia; Otto, Marthe; Hartl, Günther B; Petersen, Britt; Honnen, Ann-Christin

    2009-04-01

    We analyzed 121 golden jackals (Canis aureus) from six sample sites in Serbia with regard to genetic variability and differentiation as revealed by mitochondrial control region sequences and eight nuclear microsatellite loci. There was no variation at all in the mtDNA sequences, and nuclear variability was very low (average observed and expected heterozygosity of 0.29 and 0.34, respectively). This is in line with the considerable recent range expansion of this species in the Balkans and indicates a strong founder effect in the recently established Serbian population. We did not find evidence of differentiation between the northeastern jackals and those from the plain of Srem or those in between. F-statistics and Bayesian Structure analyses, however, were indicative of a low degree of overall differentiation in the Serbian population. A vagrant Austrian jackal that was also analyzed was genetically indistinguishable from its Serbian conspecifics. PMID:19169806

  11. Mapping the gene for hereditary hyperparathyroidism and prolactinoma (MENI[sub Burin]) to chromosome 11q: Evidence for a founder effect in patients from Newfoundland

    SciTech Connect

    Petty, E.M.; Bale, A.E. ); Green, J.S. ); Marx, S.J. ); Taggart, R.T. ); Farid, N. )

    1994-06-01

    An autosomal dominant syndrome of prolactinomas, carcinoids, and hyperparathyroidism was described in four Newfoundland kindreds in 1980 and in one kindred from the Pacific Northwest in 1983. Because this syndrome shares many features with multiple endocrine neoplasia type 1, the gene for which maps to proximal chromosome 11q, the authors performed linkage studies with chromosome 11 markers in prolactinoma families to determine whether the two genes map to the same location. All proximal chromosome 11q markers gave positive LOD scores, and no recombinants were seen with PYGM (LOD score 15.25, recombination fraction .0). All affected individuals from Newfoundland shared the same PYGM allele, providing evidence for a founder effect. The disease in the Pacific Northwest kindred cosegregated with a different PYGM allele. 32 refs., 2 figs., 3 tabs.

  12. Rapid Buildup of Genetic Diversity in Founder Populations of the Gynodioecious Plant Species Origanum vulgare after Semi-Natural Grassland Restoration

    PubMed Central

    Helsen, Kenny; Jacquemyn, Hans; Hermy, Martin; Vandepitte, Katrien; Honnay, Olivier

    2013-01-01

    In most landscapes the success of habitat restoration is largely dependent on spontaneous colonization of plant species. This colonization process, and the outcome of restoration practices, can only be considered successful if the genetic makeup of founding populations is not eroded through founder effects and subsequent genetic drift. Here we used 10 microsatellite markers to investigate the genetic effects of recent colonization of the long-lived gynodioecious species Origanum vulgare in restored semi-natural grassland patches. We compared the genetic diversity and differentiation of fourteen recent populations with that of thirteen old, putative source populations, and we evaluated the effects of spatial configuration of the populations on colonization patterns. We did not observe decreased genetic diversity in recent populations, or inflated genetic differentiation among them. Nevertheless, a significantly higher inbreeding coefficient was observed in recent populations, although this was not associated with negative fitness effects. Overall population genetic differentiation was low (FST = 0.040). Individuals of restored populations were assigned to on average 6.1 different source populations (likely following the ‘migrant pool’ model). Gene flow was, however, affected by the spatial configuration of the grasslands, with gene flow into the recent populations mainly originating from nearby source populations. This study demonstrates how spontaneous colonization after habitat restoration can lead to viable populations in a relatively short time, overcoming pronounced founder effects, when several source populations are nearby. Restored populations can therefore rapidly act as stepping stones and sources of genetic diversity, likely increasing overall metapopulation viability of the study species. PMID:23840642

  13. Genetic and biochemical study of dual hereditary jaundice: Dubin-Johnson and Gilbert's syndromes. Haplotyping and founder effect of deletion in ABCC2.

    PubMed

    Slachtova, Lenka; Seda, Ondrej; Behunova, Jana; Mistrik, Martin; Martasek, Pavel

    2016-05-01

    Dual hereditary jaundice, a combination of Dubin-Johnson and Gilbert's syndromes, is a rare clinical entity resulting from the compound defects of bilirubin conjugation and transport. We aimed to study the hereditary jaundice in 56 members from seven seemingly unrelated Roma families, to find the causal genetic defect and to estimate its origin in Roma population. On the basis of biochemical results of total and conjugated serum bilirubin and clinical observations, ABCC2 gene, TATA box and phenobarbital enhancer (PBREM) of UGT1A1 gene were analyzed by sequencing, RFLP and fragment analysis. We found a novel variant c.1013_1014delTG in the eighth exon of ABCC2 gene in 17 individuals in homozygous state. Dual defect NG_011798.1:c.[1013_1014delTG]; NG_002601.2:g.[175492_175493insTA] in homozygous state was found in four subjects. Biochemical analyses of porphyrins and coproporphyrin isomers in urine performed by HPLC showed inverted ratio of excreted coproporphyrin, with the predominance of coproporphyrin I (up to 100%), typical for patients with Dubin-Johnson syndrome. Pursuant cultural and social specifics of the population led us to suspect a founder effect; therefore, we performed a haplotype study using genotyping data from Affymetrix Genome-Wide Human SNP Array 6.0. As a result, we detected a common 86 kbp haplotype encompassing promoter and part of the ABCC2 coding region among all families, and estimated the age of the ancestral variant to 178-185 years. In this study, we found a novel deletion in ABCC2 gene, described genetic and biochemical features of dual hereditary jaundice and confirmed the existence of founder effect and common haplotype among seven Roma families. PMID:26350512

  14. Clinical expression and new SPINK5 splicing defects in Netherton syndrome: unmasking a frequent founder synonymous mutation and unconventional intronic mutations.

    PubMed

    Lacroix, Matthieu; Lacaze-Buzy, Laetitia; Furio, Laetitia; Tron, Elodie; Valari, Manthoula; Van der Wier, Gerda; Bodemer, Christine; Bygum, Anette; Bursztejn, Anne-Claire; Gaitanis, George; Paradisi, Mauro; Stratigos, Alexander; Weibel, Lisa; Deraison, Céline; Hovnanian, Alain

    2012-03-01

    Netherton syndrome (NS) is a severe skin disease caused by loss-of-function mutations in SPINK5 (serine protease inhibitor Kazal-type 5) encoding the serine protease inhibitor LEKTI (lympho-epithelial Kazal type-related inhibitor). Here, we disclose new SPINK5 defects in 12 patients, who presented a clinical triad suggestive of NS with variations in inter- and intra-familial disease expression. We identified a new and frequent synonymous mutation c.891C>T (p.Cys297Cys) in exon 11 of the 12 NS patients. This mutation disrupts an exonic splicing enhancer sequence and causes out-of-frame skipping of exon 11. Haplotype analysis indicates that this mutation is a founder mutation in Greece. Two other new deep intronic mutations, c.283-12T>A in intron 4 and c.1820+53G>A in intron 19, induced partial intronic sequence retention. A new nonsense c.2557C>T (p.Arg853X) mutation was also identified. All mutations led to a premature termination codon resulting in no detectable LEKTI on skin sections. Two patients with deep intronic mutations showed residual LEKTI fragments in cultured keratinocytes. These fragments retained some functional activity, and could therefore, together with other determinants, contribute to modulate the disease phenotype. This new founder mutation, the most frequent mutation described in European populations so far, and these unusual intronic mutations, widen the clinical and molecular spectrum of NS and offer new diagnostic perspectives for NS patients. PMID:22089833

  15. Genetic and morphometric evidence on a Galápagos Island exposes founder effects and diversification in the first-known (truly) feral western dog population.

    PubMed

    Reponen, Sini E M; Brown, Sarah K; Barnett, Bruce D; Sacks, Benjamin N

    2014-02-01

    Domesticated animals that revert to a wild state can become invasive and significantly impact native biodiversity. Although dogs can be problematic locally, only the Australasian dingo is known to occur in isolation from humans. Western dogs have experienced more intense artificial selection, which potentially limits their invasiveness. However, feral dogs eradicated from Isabela Island, Galápagos in the 1980s could be the first-known exception. We used DNA and morphometric data from 92 of these dogs to test the hypotheses that (i) these dogs persisted independently of humans for up to a century and a half since descending from a handful of dogs introduced in the early 1800s, vs. (ii) similarly to other western feral dog populations, they reflected continuous recruitment of strays from human settlements on a portion of the Island. We detected one dominant maternal lineage and one dominant paternal lineage shared by the three subpopulations, along with low autosomal genetic diversity, consistent with the hypothesized common origins from a small founder population. Genetic diversity patterns among the three island subpopulations were consistent with stepping-stone founder effects, while morphometric differentiation suggested rapid phenotypic divergence, possibly due to drift and reinforced by selection corresponding to distinct microclimates and habitats on Isabela. Despite the continued presence of free-ranging dogs in the vicinity of settlements on Isabela and other Galápagos Islands, feral populations have not reestablished in remote areas since the 1980s, emphasizing the rarity of conditions necessary for feralization of modern western dogs. PMID:24261528

  16. Formation of low-δ18O magmas of the Kangerlussuaq Intrusion by addition of water derived from dehydration of foundered basaltic roof rocks

    NASA Astrophysics Data System (ADS)

    Riishuus, Morten S.; Harris, Chris; Peate, David W.; Tegner, Christian; Wilson, J. Richard; Brooks, C. Kent

    2015-05-01

    The Kangerlussuaq Intrusion in East Greenland is concentrically zoned from quartz nordmarkite (quartz syenite) at the margin, through pulaskite, to foyaite (nepheline syenite) in the centre, with no apparent intrusive contacts. The δ18O values of coexisting minerals are consistent with oxygen isotope equilibrium at magmatic temperatures. Most of the intrusion formed from low-δ18O magma; magma δ18O values generally increased upwards from about 3.3 ‰ in the quartz nordmarkites to 5.6 ‰ in the foyaites. The lowest magma δ18O value of about -1.0 ‰ is from the upper part of the nordmarkites, where there is a high concentration of foundered basaltic xenoliths (stoped from the roof of the intrusion). The amphiboles in the syenites have δD values that range from those typical of hydrous mantle-derived minerals to much lower values (-86 to -157 ‰), as do whole-rock samples of xenolith and country rock (-125 to -148 ‰). The low magma δ18O and δD values are consistent with continuous incorporation, exchange and upward escape of low-δ18O and δD fluids released from stoped basaltic roof material. Mass balance suggests that the integrated amount of water involved was 7 wt% of the volume of the magma, but locally reached 30 wt% water. The requirement for large amounts of water with low δ18O value is satisfied only if the foundered basalt contained most of its water in cavities as opposed to hydrous minerals. Even with this requirement, the volume of stoped basalt would have been equal to the volume of the magma. Repeated recharge of the residual magma with progressively less contaminated silica undersaturated melt resulted in a gradual shift across the low-pressure thermal divide. Crystallisation was suppressed by the depression of the liquidus due to water saturation of the residual magma (pH2O ~1 kbar).

  17. A highly recombined, high-density, eight-founder wheat MAGIC map reveals extensive segregation distortion and genomic locations of introgression segments.

    PubMed

    Gardner, Keith A; Wittern, Lukas M; Mackay, Ian J

    2016-06-01

    Multiparent Advanced Generation Intercross (MAGIC) mapping populations offer unique opportunities and challenges for marker and QTL mapping in crop species. We have constructed the first eight-parent MAGIC genetic map for wheat, comprising 18 601 SNP markers. We validated the accuracy of our map against the wheat genome sequence and found an improvement in accuracy compared to published genetic maps. Our map shows a notable increase in precision resulting from the three generations of intercrossing required to create the population. This is most pronounced in the pericentromeric regions of the chromosomes. Sixteen percent of mapped markers exhibited segregation distortion (SD) with many occurring in long (>20 cM) blocks. Some of the longest and most distorted blocks were collinear with noncentromeric high-marker-density regions of the genome, suggesting they were candidates for introgression fragments introduced into the bread wheat gene pool from other grass species. We investigated two of these linkage blocks in detail and found strong evidence that one on chromosome 4AL, showing SD against the founder Robigus, is an interspecific introgression fragment. The completed map is available from http://www.niab.com/pages/id/326/Resources. PMID:26801965

  18. A novel MERTK deletion is a common founder mutation in the Faroe Islands and is responsible for a high proportion of retinitis pigmentosa cases

    PubMed Central

    Duno, Morten; Batbayli, Mustafa; Vilhelmsen, Kaj; Rosenberg, Thomas

    2011-01-01

    Purpose The aim of the study was to elucidate the genetic background of retinitis pigmentosa (RP) in a Faroe Islands population, a genetic isolate in the North Atlantic Ocean. Methods Blood samples were collected from subjects diagnosed with RP and their families. DNA from affected individuals underwent single nucleotide polymorphism microarray analysis and homozygosity mapping followed by sequence analysis of candidate genes. Results We identified 25 cases of nonsyndromic RP corresponding to a prevalence of 1 in 1,900. Single nucleotide polymorphism analysis revealed a homozygous region on chromosome 2q, common to patients in four families, which harbored the RP gene MER tyrosine kinase protooncogene (MERTK). A deletion of 91 kb was identified in seven patients, representing 30% of the analyzed Faroese cases of nonsyndromic RP. The clinical course of six patients who were homozygous for the deletion showed onset in the first decade followed by a rapid deterioration of both rod and cone photoreceptor function. Early macular involvement was present, in accordance with that of other reported patients with MERTK mutations. Conclusions Previous studies have shown a frequency of less than 1% of MERTK mutations in RP patients. The 91-kb deletion encompassing exons 1–7 of MERTK is a common founder mutation in the Faroe Islands, responsible for around 30% of RP, and together with mutations in protocadherin 21 (PCDH21) accounts for more than half of the retinal dystrophy cases. PMID:21677792

  19. BRCA Genetic Screening in Middle Eastern and North African: Mutational Spectrum and Founder BRCA1 Mutation (c.798_799delTT) in North African

    PubMed Central

    Laraqui, Abdelilah; Uhrhammer, Nancy; EL Rhaffouli, Hicham; Sekhsokh, Yassine; Lahlou-Amine, Idriss; Bajjou, Tahar; Hilali, Farida; El Baghdadi, Jamila; Al Bouzidi, Abderrahmane; Bakri, Youssef; Amzazi, Said; Bignon, Yves-Jean

    2015-01-01

    Background. The contribution of BRCA1 mutations to both hereditary and sporadic breast and ovarian cancer (HBOC) has not yet been thoroughly investigated in MENA. Methods. To establish the knowledge about BRCA1 mutations and their correlation with the clinical aspect in diagnosed cases of HBOC in MENA populations. A systematic review of studies examining BRCA1 in BC women in Cyprus, Jordan, Egypt, Lebanon, Morocco, Algeria, and Tunisia was conducted. Results. Thirteen relevant references were identified, including ten studies which performed DNA sequencing of all BRCA1 exons. For the latter, 31 mutations were detected in 57 of the 547 patients ascertained. Familial history of BC was present in 388 (71%) patients, of whom 50 were mutation carriers. c.798_799delTT was identified in 11 North African families, accounting for 22% of total identified BRCA1 mutations, suggesting a founder allele. A broad spectrum of other mutations including c.68_69delAG, c.181T>G, c.5095C>T, and c.5266dupC, as well as sequence of unclassified variants and polymorphisms, was also detected. Conclusion. The knowledge of genetic structure of BRCA1 in MENA should contribute to the assessment of the necessity of preventive programs for mutation carriers and clinical management. The high prevalence of BC and the presence of frequent mutations of the BRCA1 gene emphasize the need for improving screening programs and individual testing/counseling. PMID:25814778

  20. A Founder Effect of c.257 + 2T > C Mutation in NCF2 Gene Underlies Severe Chronic Granulomatous Disease in Eleven Patients.

    PubMed

    Ben-Farhat, Khaoula; Ben-Mustapha, Imen; Ben-Ali, Meriem; Rouault, Karen; Hamami, Saber; Mekki, Najla; Ben-Chehida, Amel; Larguèche, Beya; Fitouri, Zohra; Abdelmoula, Selim; Khemiri, Monia; Guediche, Mohamed-Neji; Boukthir, Samir; Barsaoui, Sihem; Chemli, Jalel; Barbouche, Mohamed-Ridha

    2016-08-01

    Chronic granulomatous disease (CGD) is the prototypic functional neutrophil disorder caused by genetic defects in one of the five genes encoding the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase subunits of phagocytes. Mutations causing the most prevalent form of CGD in western populations are located in the X-linked-CYBB gene. The four remaining autosomal recessive (AR) forms collectively account for one-third of CGD cases. We investigated the clinical and molecular features of eleven patients with CGD from 6 consanguineous families, originating from contiguous regions in the west of Tunisia. The patients' clinical phenotype is characterized by a high incidence of mycobacterial infections. Five out of the eleven patients died despite treatment arguing in favor of a severe clinical form of CGD. These findings correlated with the absence of functional p67phox protein as well as the absence of residual reactive oxygen intermediates (ROI) production. Genetic analysis showed the presence, in all patients, of a unique mutation (c.257 + 2T > C) in NCF2 gene predicted to affect RNA splicing. Segregating analysis using nine polymorphic markers overlapping the NCF2 gene revealed a common haplotype spanning 4.1 Mb. The founder event responsible for this mutation was estimated to have arisen approximately 175 years ago. These findings will facilitate the implementation of preventive approaches through genetic counseling in affected consanguineous families. PMID:27220316

  1. The initiation of lateral roots in the primary roots of maize (Zea mays L.) implies a reactivation of cell proliferation in a group of founder pericycle cells.

    PubMed

    Alarcón, M Victoria; Lloret, Pedro G; Martín-Partido, Gervasio; Salguero, Julio

    2016-03-15

    The initiation of lateral roots (LRs) has generally been viewed as a reactivation of proliferative activity in pericycle cells that are committed to initiate primordia. However, it is also possible that pericycle founder cells that initiate LRs never cease proliferative activity but rather are displaced to the most distal root zones while undertaking successive stages of LR initiation. In this study, we tested these two alternative hypotheses by examining the incorporation of 5-bromo-2'-deoxyuridine (BrdU) into the DNA of meristematic root cells of Zea mays. According to the values for the length of the cell cycle and values for cell displacement along the maize root, our results strongly suggest that pericycle cells that initiate LR primordia ceased proliferative activity upon exiting the meristematic zone. This finding is supported by the existence of a root zone between 4 and 20mm from the root cap junction, in which neither mitotic cells nor labelled nuclei were observed in phloem pericycle cells. PMID:26905196

  2. Eduardo Primo Yúfera, founder of Revista de Agroquímica y Tecnología de Alimentos and pioneer on food science and technology research in Spain.

    PubMed

    Ayala-Gascón, M; Aleixandre-Benavent, R; Gandía-Balaguer, A

    2011-12-01

    Eduardo Primo Yúfera was the founder and director of the Instituto de Agroquímica y Tecnología de Alimentos (IATA, 1957-1974) until he was appointed president of the Consejo Superior de Investigaciones Científicas (CSIC). His aim to publicize food science led him to create the Revista de Agroquímica y Tecnología de Alimentos in 1961, the forerunner of this journal, Food Science and Technology International, which he directed until 1977. Of his scientific output, 50% has been published in this journal. He is considered to be the promoter and exponent of Food Science and Technology and Chemical Ecology in Spain as well as the instigator of the country's innovation model (R&D and innovation). In his work, he was able to combine basic research excellence and socially relevant applied research to move both science and society forward. He was an example and inspiration to many colleagues and followers. The aim of this study is to highlight the influence and importance of Primo Yúfera in the formation, development and consolidation of the journal Revista de Agroquímica y Tecnología de Alimentos, and to appraise his scientific contribution to this journal. PMID:22049157

  3. Comparison of multiple genotyping methods for the identification of the cancer predisposing founder mutation p.R337H in TP53.

    PubMed

    Fitarelli-Kiehl, Mariana; Macedo, Gabriel S; Schlatter, Rosane Paixão; Koehler-Santos, Patricia; Matte, Ursula da Silveira; Ashton-Prolla, Patricia; Giacomazzi, Juliana

    2016-06-01

    Germline mutations in the TP53 gene are associated with Li-Fraumeni and Li-Fraumeni-Like Syndromes, characterized by increased predisposition to early-onset cancers. In Brazil, the prevalence of the TP53-p.R337H germline mutation is exceedingly high in the general population and in cancer-affected patients, probably as result of a founder effect. Several genotyping methods are used for the molecular diagnosis of LFS/LFL, however Sanger sequencing is still considered the gold standard. We compared performance, cost and turnaround time of Sanger sequencing, PCR-RFLP, TaqMan-PCR and HRM in the p.R337H genotyping. The performance was determined by analysis of 95 genomic DNA samples and results were 100% concordant for all methods. Sequencing was the most expensive method followed by TaqMan-PCR, PCR-RFLP and HRM. The overall cost of HRM increased with the prevalence of positive samples, since confirmatory sequencing must be performed when a sample shows an abnormal melting profile, but remained lower than all other methods when the mutation prevalence was less than 2.5%. Sequencing had the highest throughput and the longest turnaround time, while TaqMan-PCR showed the lowest turnaround and hands-on times. All methodologies studied are suitable for the detection of p.R337H and the choice will depend on the application and clinical scenario. PMID:27275664

  4. A novel Gypsy founder mutation, p.Arg1109X in the CMT4C gene, causes variable peripheral neuropathy phenotypes

    PubMed Central

    Gooding, R; Colomer, J; King, R; Angelicheva, D; Marns, L; Parman, Y; Chandler, D; Bertranpetit, J; Kalaydjieva, L

    2005-01-01

    Background: Linkage, haplotype and sequencing analysis in a large Spanish Gypsy kindred with multiple members affected by autosomal recessive peripheral neuropathy led to the identification of a novel mutation, p.Arg1109X, in the CMT4C gene. The screening of further unrelated patients, and of a panel of ethnically matched controls, showed that p.Arg1109X is an ancestral mutation which occurs in Gypsy populations across Europe and is the most common cause of autosomal recessive Charcot–Marie–Tooth disease in Spanish Gypsies. Objective: To report the identification of a novel Gypsy founder mutation causing autosomal recessive CMT4C disease in a sample of homozygous affected individuals. Results: The mutation was associated with a surprisingly broad spectrum of neuropathy phenotypes, with variation in the age at onset, rate of progression, severity of muscle and sensory involvement, the presence of scoliosis, and cranial nerve involvement. Conclusions: Ascertainment and further studies of CMT4C patients in this population will provide a unique opportunity for characterising the full range of clinical manifestations of the disease in a genetically homogeneous sample. PMID:16326826

  5. Advancing paternal age at birth is associated with poorer social functioning earlier and later in life of schizophrenia patients in a founder population.

    PubMed

    Liebenberg, Rudolf; van Heerden, Brigitte; Ehlers, René; Du Plessis, Anna M E; Roos, J Louw

    2016-09-30

    Consistent associations have been found between advanced paternal age and an increased risk of psychiatric disorders, such as schizophrenia, in their offspring. This increase appears to be linear as paternal age increases. The present study investigates the relationship between early deviant behaviour in the first 10 years of life of patients as well as longer term functional outcome and paternal age in sporadic Afrikaner founder population cases of schizophrenia. This might improve our understanding of Paternal Age-Related Schizophrenia (PARS). Follow-up psychiatric diagnoses were confirmed by the Diagnostic Interview for Genetic Studies (DIGS). An early deviant childhood behaviour semi-structured questionnaire and the Specific Level of Functioning Assessment (SLOF) were completed. From the logistic regression models fitted, a significant negative relationship was found between paternal age at birth and social dysfunction as early deviant behaviour. Additionally, regression analysis revealed a significant negative relationship between paternal age at birth and the SLOF for interpersonal relationships later in life. Early social dysfunction may represent a phenotypic trait for PARS. Further research is required to understand the relationship between early social dysfunction and deficits in interpersonal relationships later in life. PMID:27416538

  6. Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome.

    PubMed

    Cartault, François; Munier, Patrick; Jacquemont, Marie-Line; Vellayoudom, Jeannine; Doray, Bérénice; Payet, Christine; Randrianaivo, Hanitra; Laville, Jean-Marc; Munnich, Arnold; Cormier-Daire, Valérie

    2015-01-01

    First described as a variant of Larsen syndrome in Reunion Island (LRS) in the southern Indian Ocean, 'Larsen of Reunion Island syndrome' is characterized by dwarfism, hyperlaxity, multiple dislocations and distinctive facial features. It overlaps with Desbuquois dysplasia, Larsen syndrome and spondyloepiphyseal dysplasia with dislocations ascribed to CANT1, FLNB and CHST3 mutations, respectively. We collected the samples of 22 LRS cases. After exclusion of CANT1, FLNB and CHST3 genes, an exome sequencing was performed in two affected second cousins and one unaffected sister. We identified a homozygous missense mutation in B4GALT7, NM_007255.2: c.808C>T p.(Arg270Cys) named p.R270C, in the two affected cases, not present in the unaffected sister. The same homozygous mutation was subsequently identified in the remaining 20 LRS cases. Our findings demonstrate that B4GALT7 is the causative gene for LRS. The identification of a unique homozygous mutation argues in favor of a founder effect. B4GALT7 encodes a galactosyltransferase, required for the initiation of glycoaminoglycan side chain synthesis of proteoglycans. This study expands the phenotypic spectrum of B4GALT7 mutations, initially described as responsible for the progeroid variant of Ehlers-Danlos syndrome. It further supports a common physiopathological basis involving proteoglycan synthesis in skeletal disorders with dislocations. PMID:24755949

  7. AmericaPlex26: A SNaPshot Multiplex System for Genotyping the Main Human Mitochondrial Founder Lineages of the Americas

    PubMed Central

    Coutinho, Alexandra; Valverde, Guido; Fehren-Schmitz, Lars; Cooper, Alan; Barreto Romero, Maria Inés; Espinoza, Isabel Flores; Llamas, Bastien; Haak, Wolfgang

    2014-01-01

    Phylogeographic studies have described a reduced genetic diversity in Native American populations, indicative of one or more bottleneck events during the peopling and prehistory of the Americas. Classical sequencing approaches targeting the mitochondrial diversity have reported the presence of five major haplogroups, namely A, B, C, D and X, whereas the advent of complete mitochondrial genome sequencing has recently refined the number of founder lineages within the given diversity to 15 sub-haplogroups. We developed and optimized a SNaPshot assay to study the mitochondrial diversity in pre-Columbian Native American populations by simultaneous typing of 26 single nucleotide polymorphisms (SNPs) characterising Native American sub-haplogroups. Our assay proved to be highly sensitive with respect to starting concentrations of target DNA and could be applied successfully to a range of ancient human skeletal material from South America from various time periods. The AmericaPlex26 is a powerful assay with enhanced phylogenetic resolution that allows time- and cost-efficient mitochondrial DNA sub-typing from valuable ancient specimens. It can be applied in addition or alternative to standard sequencing of the D-loop region in forensics, ancestry testing, and population studies, or where full-resolution mitochondrial genome sequencing is not feasible. PMID:24671218

  8. Localization of the familial Mediterranean fever gene (FMF) to a 250-kb interval in non-Ashkenazi Jewish founder haplotypes. The French FMF Consortium.

    PubMed Central

    1996-01-01

    Chromosome 16p13.3 harbors a gene (MEF) associated with familial Mediterranean fever (FMF), a recessive disease very common in populations of Mediterranean ancestry. In the course of positional cloning of MEF, we genotyped 26 non-Ashkenazi Jewish FMF pedigrees (310 meioses) with 15 microsatellite markers, most of which were recently developed by Généthon. Identification of recombination events in the haplotypes allowed narrowing of the MEF interval to a region between D16S3124 (telomeric) and D16S475 (centromeric). Two markers, D16S3070 and D16S3275, a microsatellite marker isolated from a YAC that also contains D16S3070, showed no recombination with the disease. Linkage disequilibrium and haplotype analysis highlighted the existence of a founder haplotype in our population. The core ancestral alleles were present in 71% of MEF-bearing chromosomes at loci D16S3070 and D16S3275. Furthermore, identification of historical crossing-over events in these pedigrees indicated that MEF is located between these two loci, which are both contained in a 250-kb genomic fragment. PMID:8751861

  9. Comparison of multiple genotyping methods for the identification of the cancer predisposing founder mutation p.R337H inTP53

    PubMed Central

    Fitarelli-Kiehl, Mariana; Macedo, Gabriel S.; Schlatter, Rosane Paixão; Koehler-Santos, Patricia; Matte, Ursula da Silveira; Ashton-Prolla, Patricia; Giacomazzi, Juliana

    2016-01-01

    Abstract Germline mutations in the TP53 gene are associated with Li-Fraumeni and Li-Fraumeni-Like Syndromes, characterized by increased predisposition to early-onset cancers. In Brazil, the prevalence of the TP53-p.R337H germline mutation is exceedingly high in the general population and in cancer-affected patients, probably as result of a founder effect. Several genotyping methods are used for the molecular diagnosis of LFS/LFL, however Sanger sequencing is still considered the gold standard. We compared performance, cost and turnaround time of Sanger sequencing, PCR-RFLP, TaqMan-PCR and HRM in the p.R337H genotyping. The performance was determined by analysis of 95 genomic DNA samples and results were 100% concordant for all methods. Sequencing was the most expensive method followed by TaqMan-PCR, PCR-RFLP and HRM. The overall cost of HRM increased with the prevalence of positive samples, since confirmatory sequencing must be performed when a sample shows an abnormal melting profile, but remained lower than all other methods when the mutation prevalence was less than 2.5%. Sequencing had the highest throughput and the longest turnaround time, while TaqMan-PCR showed the lowest turnaround and hands-on times. All methodologies studied are suitable for the detection of p.R337H and the choice will depend on the application and clinical scenario. PMID:27275664

  10. Founder Effect of a c.828+3A>T Splice Site Mutation in Peripherin 2 (PRPH2) Causing Autosomal Dominant Retinal Dystrophies

    PubMed Central

    Shankar, Suma P.; Birch, David G.; Ruiz, Richard S.; Hughbanks-Wheaton, Dianna K.; Sullivan, Lori S.; Bowne, Sara J.; Stone, Edwin M.; Daiger, Stephen P.

    2015-01-01

    single-nucleotide polymorphism) in exon 3 of PRPH2, suggesting this mutation is from a common ancestor and is a founder mutation. It has a prevalence of 2% in families diagnosed as having autosomal dominant retinitis pigmentosa and 10% in families with variable clinical diagnosis of pattern, macular, and retinal dystrophies. Individuals with the c.828+3A>T mutation expressed a PRPH2 transcript not found in control participants and that was consistent with abnormal splicing. Conclusions and Relevance The PRPH2 c.828+3A>T splice site mutation is a frequent cause of inherited retinal dystrophies and is owing to the founder effect. The likely cause of disease is the missplicing of the PRPH2 message that results in a truncated protein product. Identifying the genetic etiology assists in more accurate management and possible future therapeutic options. PMID:25675413

  11. Evolutionary History of the Live-Bearing Endemic Allotoca diazi Species Complex (Actinopterygii, Goodeinae): Evidence of Founder Effect Events in the Mexican Pre-Hispanic Period.

    PubMed

    Corona-Santiago, Diushi Keri; Doadrio, Ignacio; Domínguez-Domínguez, Omar

    2015-01-01

    The evolutionary history of Mexican ichthyofauna has been strongly linked to natural events, and the impact of pre-Hispanic cultures is little known. The live-bearing fish species Allotoca diazi, Allotoca meeki and Allotoca catarinae occur in areas of biological, cultural and economic importance in central Mexico: Pátzcuaro basin, Zirahuén basin, and the Cupatitzio River, respectively. The species are closely related genetically and morphologically, and hypotheses have attempted to explain their systematics and biogeography. Mitochondrial DNA and microsatellite markers were used to investigate the evolutionary history of the complex. The species complex shows minimal genetic differentiation. The separation of A. diazi and A. meeki was dated to 400-7000 years ago, explained by geological and climate events. A bottleneck and reduction of genetic diversity in Allotoca diazi was detected, attributed to recent climate fluctuations and anthropogenic activity. The isolation of A. catarinae occurred ~1900 years ago. No geological events are documented in the area during this period, but the date is contemporary with P'urhépecha culture settlements. This founder effect represents the first evidence of fish species translocation by a pre-Hispanic culture of Mexico. The response of the complex to climate fluctuation, geological changes and human activity in the past and the future according to the ecological niches predictions indicates areas of vulnerability and important information for conservation. The new genetic information showed that the Allotoca diazi complex consist of two genetic groups with an incomplete lineage sorting pattern: Pátzcuaro and Zirahuén lakes, and an introduced population in the Cupatitzio River. PMID:25946217

  12. The roles of geography and founder effects in promoting host-associated differentiation in the generalist bogus yucca moth Prodoxus decipiens.

    PubMed

    Darwell, C T; Fox, K A; Althoff, D M

    2014-12-01

    There is ample evidence that host shifts in plant-feeding insects have been instrumental in generating the enormous diversity of insects. Changes in host use can cause host-associated differentiation (HAD) among populations that may lead to reproductive isolation and eventual speciation. The importance of geography in facilitating this process remains controversial. We examined the geographic context of HAD in the wide-ranging generalist yucca moth Prodoxus decipiens. Previous work demonstrated HAD among sympatric moth populations feeding on two different Yucca species occurring on the barrier islands of North Carolina, USA. We assessed the genetic structure of P. decipiens across its entire geographic and host range to determine whether HAD is widespread in this generalist herbivore. Population genetic analyses of microsatellite and mtDNA sequence data across the entire range showed genetic structuring with respect to host use and geography. In particular, genetic differentiation was relatively strong between mainland populations and those on the barrier islands of North Carolina. Finer scale analyses, however, among sympatric populations using different host plant species only showed significant clustering based on host use for populations on the barrier islands. Mainland populations did not form population clusters based on host plant use. Reduced genetic diversity in the barrier island populations, especially on the derived host, suggests that founder effects may have been instrumental in facilitating HAD. In general, results suggest that the interplay of local adaptation, geography and demography can determine the tempo of HAD. We argue that future studies should include comprehensive surveys across a wide range of environmental and geographic conditions to elucidate the contribution of various processes to HAD. PMID:25403722

  13. Mucosal Immunization of Lactating Female Rhesus Monkeys with a Transmitted/Founder HIV-1 Envelope Induces Strong Env-Specific IgA Antibody Responses in Breast Milk

    PubMed Central

    Fouda, Genevieve G. A.; Amos, Joshua D.; Wilks, Andrew B.; Pollara, Justin; Ray, Caroline A.; Chand, Anjali; Kunz, Erika L.; Liebl, Brooke E.; Whitaker, Kaylan; Carville, Angela; Smith, Shannon; Colvin, Lisa; Pickup, David J.; Staats, Herman F.; Overman, Glenn; Eutsey-Lloyd, Krissey; Parks, Robert; Chen, Haiyan; LaBranche, Celia; Barnett, Susan; Tomaras, Georgia D.; Ferrari, Guido; Montefiori, David C.; Liao, Hua-Xin; Letvin, Norman L.; Haynes, Barton F.

    2013-01-01

    We previously demonstrated that vaccination of lactating rhesus monkeys with a DNA prime/vector boost strategy induces strong T-cell responses but limited envelope (Env)-specific humoral responses in breast milk. To improve vaccine-elicited antibody responses in milk, hormone-induced lactating rhesus monkeys were vaccinated with a transmitted/founder (T/F) HIV Env immunogen in a prime-boost strategy modeled after the moderately protective RV144 HIV vaccine. Lactating rhesus monkeys were intramuscularly primed with either recombinant DNA (n = 4) or modified vaccinia virus Ankara (MVA) poxvirus vector (n = 4) expressing the T/F HIV Env C.1086 and then boosted twice intramuscularly with C.1086 gp120 and the adjuvant MF59. The vaccines induced Env-binding IgG and IgA as well as neutralizing and antibody-dependent cellular cytotoxicity (ADCC) responses in plasma and milk of most vaccinated animals. Importantly, plasma neutralization titers against clade C HIV variants MW965 (P = 0.03) and CAP45 (P = 0.04) were significantly higher in MVA-primed than in DNA-primed animals. The superior systemic prime-boost regimen was then compared to a mucosal-boost regimen, in which animals were boosted twice intranasally with C.1086 gp120 and the TLR 7/8 agonist R848 following the same systemic prime. While the systemic and mucosal vaccine regimens elicited comparable levels of Env-binding IgG antibodies, mucosal immunization induced significantly stronger Env-binding IgA responses in milk (P = 0.03). However, the mucosal regimen was not as potent at inducing functional IgG responses. This study shows that systemic MVA prime followed by either intranasal or systemic protein boosts can elicit strong humoral responses in breast milk and may be a useful strategy to interrupt postnatal HIV-1 transmission. PMID:23596289

  14. Genomic Profiling of Collaborative Cross Founder Mice Infected with Respiratory Viruses Reveals Novel Transcripts and Infection-Related Strain-Specific Gene and Isoform Expression

    PubMed Central

    Xiong, Hao; Morrison, Juliet; Ferris, Martin T.; Gralinski, Lisa E.; Whitmore, Alan C.; Green, Richard; Thomas, Matthew J.; Tisoncik-Go, Jennifer; Schroth, Gary P.; Pardo-Manuel de Villena, Fernando; Baric, Ralph S.; Heise, Mark T.; Peng, Xinxia; Katze, Michael G.

    2014-01-01

    Genetic variation between diverse mouse species is well-characterized, yet existing knowledge of the mouse transcriptome comes largely from one mouse strain (C57BL/6J). As such, it is unlikely to reflect the transcriptional complexity of the mouse species. Gene transcription is dynamic and condition-specific; therefore, to better understand the mouse transcriptional response to respiratory virus infection, we infected the eight founder strains of the Collaborative Cross with either influenza A virus or severe acute respiratory syndrome coronavirus and sequenced lung RNA samples at 2 and 4 days after infection. We found numerous instances of transcripts that were not present in the C57BL/6J reference annotation, indicating that a nontrivial proportion of the mouse genome is transcribed but poorly annotated. Of these novel transcripts, 2150 could be aligned to human or rat genomes, but not to existing mouse genomes, suggesting functionally conserved sequences not yet recorded in mouse genomes. We also found that respiratory virus infection induced differential expression of 4287 splicing junctions, resulting in strain-specific isoform expression. Of these, 59 were influenced by strain-specific mutations within 2 base pairs of key intron–exon boundaries, suggesting cis-regulated expression. Our results reveal the complexity of the transcriptional response to viral infection, previously undocumented genomic elements, and extensive diversity in the response across mouse strains. These findings identify hitherto unexplored transcriptional patterns and undocumented transcripts in genetically diverse mice. Host genetic variation drives the complexity and diversity of the host response by eliciting starkly different transcriptional profiles in response to a viral infection. PMID:24902603

  15. Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers

    PubMed Central

    Shankar, Suma P.; Hughbanks-Wheaton, Dianna K.; Birch, David G.; Sullivan, Lori S.; Conneely, Karen N.; Bowne, Sara J.; Stone, Edwin M.; Daiger, Stephen P.

    2016-01-01

    Purpose We determined the phenotypic variation, disease progression, and potential modifiers of autosomal dominant retinal dystrophies caused by a splice site founder mutation, c.828+3A>T, in the PRPH2 gene. Methods A total of 62 individuals (19 families) harboring the PRPH2 c.828+3A>T mutation, had phenotype analysis by fundus appearance, electrophysiology, and visual fields. The PRPH2 haplotypes in trans were sequenced for potential modifying variants and generalized estimating equations (GEE) used for statistical analysis. Results Several distinct phenotypes caused by the PRPH2 c.828+3A>T mutation were observed and fell into two clinical categories: Group I (N = 44) with mild pattern dystrophies (PD) and Group II (N = 18) with more severe cone-rod dystrophy (CRD), retinitis pigmentosa (RP), and central areolar chorioretinal dystrophy (CACD). The PRPH2 Gln304-Lys310-Asp338 protein haplotype in trans was found in Group I only (29.6% vs. 0%), whereas the Glu304-Lys310-Gly338 haplotype was predominant in Group II (94.4% vs. 70.4%). Generalized estimating equations analysis for PD versus the CRD/CACD/RP phenotypes in individuals over 43 years alone with the PRPH2 haplotypes in trans and age as predictors, adjusted for correlation within families, confirmed a significant effect of haplotype on severity (P = 0.03) with an estimated odds ratio of 7.16 (95% confidence interval [CI] = [2.8, 18.4]). Conclusions The PRPH2 c.828+3A>T mutation results in multiple distinct phenotypes likely modified by protein haplotypes in trans; the odds of having the CACD/RP-like phenotype (versus the PD phenotype) are 7.16 times greater with a Glu304-Lys310-Gly338 haplotype in trans. Further functional studies of the modifying haplotypes in trans and PRPH2 splice variants may offer therapeutic targets. PMID:26842753

  16. Evolutionary History of the Live-Bearing Endemic Allotoca diazi Species Complex (Actinopterygii, Goodeinae): Evidence of Founder Effect Events in the Mexican Pre-Hispanic Period

    PubMed Central

    Corona-Santiago, Diushi Keri; Doadrio, Ignacio; Domínguez-Domínguez, Omar

    2015-01-01

    The evolutionary history of Mexican ichthyofauna has been strongly linked to natural events, and the impact of pre-Hispanic cultures is little known. The live-bearing fish species Allotoca diazi, Allotoca meeki and Allotoca catarinae occur in areas of biological, cultural and economic importance in central Mexico: Pátzcuaro basin, Zirahuén basin, and the Cupatitzio River, respectively. The species are closely related genetically and morphologically, and hypotheses have attempted to explain their systematics and biogeography. Mitochondrial DNA and microsatellite markers were used to investigate the evolutionary history of the complex. The species complex shows minimal genetic differentiation. The separation of A. diazi and A. meeki was dated to 400–7000 years ago, explained by geological and climate events. A bottleneck and reduction of genetic diversity in Allotoca diazi was detected, attributed to recent climate fluctuations and anthropogenic activity. The isolation of A. catarinae occurred ~1900 years ago. No geological events are documented in the area during this period, but the date is contemporary with P’urhépecha culture settlements. This founder effect represents the first evidence of fish species translocation by a pre-Hispanic culture of Mexico. The response of the complex to climate fluctuation, geological changes and human activity in the past and the future according to the ecological niches predictions indicates areas of vulnerability and important information for conservation. The new genetic information showed that the Allotoca diazi complex consist of two genetic groups with an incomplete lineage sorting pattern: Pátzcuaro and Zirahuén lakes, and an introduced population in the Cupatitzio River. PMID:25946217

  17. Brain Invasion by CD4(+) T Cells Infected with a Transmitted/Founder HIV-1BJZS7 During Acute Stage in Humanized Mice.

    PubMed

    Wu, Xilin; Liu, Li; Cheung, Ka-Wai; Wang, Hui; Lu, Xiaofan; Cheung, Allen Ka Loon; Liu, Wan; Huang, Xiuyan; Li, Yanlei; Chen, Zhiwei W; Chen, Samantha M Y; Zhang, Tong; Wu, Hao; Chen, Zhiwei

    2016-09-01

    Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) is one of the common causes of cognitive dysfunction and morbidity among infected patients. However, to date, it remains unknown if a transmitted/founder (T/F) HIV-1 leads to neurological disorders during acute phase of infection. Since it is impossible to answer this question in humans, we studied NOD.Cg-Prkdc scid Il2rgtm1Wjl/SzJ mice (NSG) reconstituted with human PBMC (NSG-HuPBL), followed by the peritoneal challenge with the chronic HIV-1JR-FL and the T/F HIV-1BJZS7, respectively. By measuring viral load, P24 antigenemia and P24(+) cells in peripheral blood and various tissue compartments, we found that systemic infections were rapidly established in NSG-HuPBL mice by both HIV-1 strains. Although comparable peripheral viral loads were detected during acute infection, the T/F virus appeared to cause less CD4(+) T cell loss and less numbers of infected cells in different organs and tissue compartments. Both viruses, however, invaded brains with P24(+)/CD3(+) T cells detected primarily in meninges, cerebral cortex and perivascular areas. Critically, brain infections with HIV-1JR-FL but not with HIV-1BJZS7 resulted in damaged neurons together with activated microgliosis and astrocytosis as determined by significantly increased numbers of Iba1(+) microglial cells and GFAP(+) astrocytes, respectively. The increased Iba1(+) microglia was correlated positively with levels of P24 antigenemia and negatively with numbers of NeuN(+) neurons in brains of infected animals. Our findings, therefore, indicate the establishment of two useful NSG-HuPBL models, which may facilitate future investigation of mechanisms underlying HIV-1-induced microgliosis and astrocytosis. PMID:26838362

  18. Molecular phylogenetics suggests a New Guinean origin and frequent episodes of founder-event speciation in the nectarivorous lories and lorikeets (Aves: Psittaciformes).

    PubMed

    Schweizer, Manuel; Wright, Timothy F; Peñalba, Joshua V; Schirtzinger, Erin E; Joseph, Leo

    2015-09-01

    The lories and lorikeets (Aves: Loriinae: Loriini) are a readily recognizable, discrete group of nectarivorous parrots confined to the Indo-Pacific region between Wallace's Line and the Pitcairn Island group in the central-east Pacific Ocean. We present the first phylogenetic analysis of all currently recognized genera in the group using two mitochondrial and five nuclear loci. Our analyses suggest a New Guinean origin for the group at about 10million years ago (95% HPD 4.8-14.8) but this origin must be interpreted within the context of that island's complicated, recent geological history. That is, the origin and early diversification of the group may have taken place as New Guinea's Central Cordillera arose and the final constituent terranes that form present-day New Guinea were accreted. The latter activity may have promoted dispersal as a key element in the group's history. We have detected several instances of dispersal out of New Guinea that we argue constitute instances of founder-event speciation. Some phenotypically cohesive genera are affirmed as monophyletic but other genera are clearly in need of taxonomic dismantlement and reclassification. We recognize Parvipsitta Mathews, 1916 for two species usually placed in Glossopsitta and we advocate transfer of Chalcopsitta cardinalis into Pseudeos Peters, 1935. Other non-monophyletic genera such as Charmosyna, Psitteuteles and, probably, Trichoglossus, require improved taxon sampling and further phylogenetic analysis before their systematics can be resolved. Cursory examination of trait mapping across the group suggests that many traits are ancestral and of little use in determining genus-level systematics. PMID:25929786

  19. Penetrance of HNPCC-related cancers in a retrolective cohort of 12 large Newfoundland families carrying a MSH2 founder mutation: an evaluation using modified segregation models

    PubMed Central

    Kopciuk, Karen A; Choi, Yun-Hee; Parkhomenko, Elena; Parfrey, Patrick; McLaughlin, John; Green, Jane; Briollais, Laurent

    2009-01-01

    Background Accurate risk (penetrance) estimates for associated phenotypes in carriers of a major disease gene are important for genetic counselling of at-risk individuals. Population-specific estimates of penetrance are often needed as well. Families ascertained from high-risk disease clinics provide substantial data to estimate penetrance of a disease gene, but these estimates must be adjusted for possible specific sources of bias. Methods A cohort of 12 independently ascertained HNPCC families harbouring a founder MSH2 mutation was identified from a cancer genetics clinic in St. John's, Newfoundland, Canada. Carrier status was known for 247 family members but phenotype information on up to 85 additional relatives with unknown carrier status was available; using modified segregation models these additional individuals could be included in the analyses. Three HNPCC-related phenotypes were evaluated as age at diagnosis of: any HNPCC cancer (first cancer), colorectal cancer (CRC), and endometrial cancer (EC) for females. Results Lifetime (age 70) risk estimates for male and female carriers were similar for developing any HNPCC cancer (Males = 98.2%, 95% Confidence Interval (CI) = (93.8%, 99.9%); Females = 92.8%, 95% CI = (82.4%, 99.1%)) but female carriers experienced substantially reduced lifetime risk for developing CRC compared to male carriers (Females = 38.9%, 95% CI = (24.2%, 62.1%); Males = 84.5%, 95% CI = (67.3%, 91.3%)). Female non-carriers had very low lifetime risk for these two outcomes while male non-carriers had lifetime risks intermediate to the female carriers and non-carriers. Female carriers had a lifetime risk of developing EC of 82.4%. Relative risks for developing any HNPCC cancer (carriers relative to non-carriers) were substantially greater for females compared to their male counterparts (Females = 54.8, 95%CI = (4.4, 379.8); Males = 9.7, 95% CI = (0.3, 23.8)). Relative risks for developing CRC at age 70 were substantially greater for females

  20. Human non-neutralizing HIV-1 envelope monoclonal antibodies limit the number of founder viruses during SHIV mucosal infection in rhesus macaques

    SciTech Connect

    Santra, Sampa; Tomaras, Georgia D.; Warrier, Ranjit; Nicely, Nathan I.; Liao, Hua -Xin; Pollara, Justin; Liu, Pinghuang; Alam, S. Munir; Zhang, Ruijun; Cocklin, Sarah L.; Shen, Xiaoying; Duffy, Ryan; Xia, Shi -Mao; Schutte, Robert J.; Pemble IV, Charles W.; Dennison, S. Moses; Li, Hui; Chao, Andrew; Vidnovic, Kora; Evans, Abbey; Klein, Katja; Kumar, Amit; Robinson, James; Landucci, Gary; Forthal, Donald N.; Montefiori, David C.; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Pitisuttithum, Punnee; Rerks-Ngarm, Supachai; Robb, Merlin L.; Michael, Nelson L.; Kim, Jerome H.; Soderberg, Kelly A.; Giorgi, Elena E.; Blair, Lily; Korber, Bette T.; Moog, Christiane; Shattock, Robin J.; Letvin, Norman L.; Schmitz, Joern E.; Moody, M. A.; Gao, Feng; Ferrari, Guido; Shaw, George M.; Haynes, Barton F.; Douek, Daniel C.

    2015-08-03

    HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4⁺ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.

  1. Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques

    PubMed Central

    Liao, Hua-Xin; Pollara, Justin; Liu, Pinghuang; Alam, S. Munir; Zhang, Ruijun; Cocklin, Sarah L.; Shen, Xiaoying; Duffy, Ryan; Xia, Shi-Mao; Schutte, Robert J.; Pemble IV, Charles W.; Dennison, S. Moses; Li, Hui; Chao, Andrew; Vidnovic, Kora; Evans, Abbey; Klein, Katja; Kumar, Amit; Robinson, James; Landucci, Gary; Forthal, Donald N.; Montefiori, David C.; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Pitisuttithum, Punnee; Rerks-Ngarm, Supachai; Robb, Merlin L.; Michael, Nelson L.; Kim, Jerome H.; Soderberg, Kelly A.; Giorgi, Elena E.; Blair, Lily; Korber, Bette T.; Moog, Christiane; Shattock, Robin J.; Schmitz, Joern E.; Moody, M. A.; Gao, Feng; Ferrari, Guido; Shaw, George M.; Haynes, Barton F.

    2015-01-01

    HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses. PMID:26237403

  2. Human non-neutralizing HIV-1 envelope monoclonal antibodies limit the number of founder viruses during SHIV mucosal infection in rhesus macaques

    DOE PAGESBeta

    Santra, Sampa; Tomaras, Georgia D.; Warrier, Ranjit; Nicely, Nathan I.; Liao, Hua -Xin; Pollara, Justin; Liu, Pinghuang; Alam, S. Munir; Zhang, Ruijun; Cocklin, Sarah L.; et al

    2015-08-03

    HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4⁺ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant regionmore » of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.« less

  3. Confirmation of a founder effect in a Northern European population of a new β-globin variant: HBB:c.23_26dup (codons 8/9 (+AGAA)).

    PubMed

    Marchi, Nina; Pissard, Serge; Cliquennois, Manuel; Vasseur, Christian; Le Metayer, Nathalie; Mereau, Claude; Jouet, Jean Pierre; Georgel, Anne-France; Genin, Emmanuelle; Rose, Christian

    2015-09-01

    β-Thalassemia is a genetic disease caused by a defect in the production of the β-like globin chain. More than 200 known different variants can lead to the disease and are mainly found in populations that have been exposed to malaria parasites. We recently described a duplication of four nucleotides in the first exon of β-globin gene in several families of patients living in Nord-Pas-de-Calais (France). Using the genotypes at 12 microsatellite markers surrounding the β-globin gene of four unrelated variant carriers plus an additional one recently discovered, we found that they shared a common haplotype indicating a founder effect that was estimated to have taken place 225 years ago (nine generations). In order to determine whether this variant arose in this region of Northern Europe or was introduced by migrants from regions of the world where thalassemia is endemic, we genotyped the first 4 unrelated variant carriers and 32 controls from Nord-Pas-de-Calais for 97 European ancestry informative markers (EAIMs). Using these EAIMs and comparing with population reference panels, we demonstrated that the variant carriers were very similar to the controls and were closer to North European populations than to South European or Middle-East populations. Rare β-thalassemia variants have already been described in patients sampled in non-endemic regions, but it is the first proof of a founder effect in Northern Europe. PMID:25469539

  4. Molecular Analysis of Hereditary Nonpolyposis Colorectal Cancer in the United States: High Mutation Detection Rate among Clinically Selected Families and Characterization of an American Founder Genomic Deletion of the MSH2 Gene

    PubMed Central

    Wagner, Anja; Barrows, Alicia; Wijnen, Juul Th.; van der Klift, Heleen; Franken, Patrick F.; Verkuijlen, Paul; Nakagawa, Hidewaki; Geugien, Marjan; Jaghmohan-Changur, Shantie; Breukel, Cor; Meijers-Heijboer, Hanne; Morreau, Hans; van Puijenbroek, Marjo; Burn, John; Coronel, Stephany; Kinarski, Yulia; Okimoto, Ross; Watson, Patrice; Lynch, Jane F.; de la Chapelle, Albert; Lynch, Henry T.; Fodde, Riccardo

    2003-01-01

    The identification of germline mutations in families with HNPCC is hampered by genetic heterogeneity and clinical variability. In previous studies, MSH2 and MLH1 mutations were found in approximately two-thirds of the Amsterdam-criteria–positive families and in much lower percentages of the Amsterdam-criteria–negative families. Therefore, a considerable proportion of HNPCC seems not to be accounted for by the major mismatch repair (MMR) genes. Does the latter result from a lack of sensitivity of mutation detection techniques, or do additional genes underlie the remaining cases? In this study we address these questions by thoroughly investigating a cohort of clinically selected North American families with HNPCC. We analyzed 59 clinically well-defined U.S. families with HNPCC for MSH2, MLH1, and MSH6 mutations. To maximize mutation detection, different techniques were employed, including denaturing gradient gel electrophoresis, Southern analysis, microsatellite instability, immunohistochemistry, and monoallelic expression analysis. In 45 (92%) of the 49 Amsterdam-criteria–positive families and in 7 (70%) of the 10 Amsterdam-criteria–negative families, a mutation was detected in one of the three analyzed MMR genes. Forty-nine mutations were in MSH2 or MLH1, and only three were in MSH6. A considerable proportion (27%) of the mutations were genomic rearrangements (12 in MSH2 and 2 in MLH1). Notably, a deletion encompassing exons 1–6 of MSH2 was detected in seven apparently unrelated families (12% of the total cohort) and was subsequently proven to be a founder. Screening of a second U.S. cohort with HNPCC from Ohio allowed the identification of two additional kindreds with the identical founder deletion. In the present study, we show that optimal mutation detection in HNPCC is achieved by combining accurate and expert clinical selection with an extensive mutation detection strategy. Notably, we identified a common North American deletion in MSH2, accounting

  5. Molecular analysis of the SRD5A2 in 46,XY subjects with incomplete virilization: the P212R substitution of the steroid 5alpha-reductase 2 may constitute an ancestral founder mutation in Mexican patients.

    PubMed

    Vilchis, Felipe; Ramos, Luis; Méndez, Juan Pablo; Benavides, Socorro; Canto, Patricia; Chávez, Bertha

    2010-01-01

    Inactivating mutations of the SRD5A2 gene result in steroid 5α-reductase 2 deficiency, an autosomal recessive disorder expressed as a male-limited disorder of sex development. Herein, genomic DNA was isolated from 11 new patients with apparent steroid 5α-reductase 2 deficiency. Coding sequence abnormalities in SRD5A2 were assessed by exon-specific polymerase chain reaction, single-stranded conformation polymorphism, and direct sequencing. Likewise, enzymatic activity of the P212R gene variant of SRD5A2 was assessed. DNA analysis revealed mutations in all patients (G115D, R171S, N193S, E197D, G203S, P212R). Three individuals were compound heterozygotes, 6 were homozygotes, and 2 more were single heterozygotes for SRD5A2 mutations; remarkably, 40% of the mutant alleles (9/22) contained the gene variant P212R. The results described in this study represent, along with our previous reports, the largest number of patients with steroid 5α-reductase 2 deficiency belonging to nonrelated families. Regarding the frequency of the p.P212R mutation in our population and its presence throughout all of our country, it allows us to hypothesize that the presence of this mutation may constitute a founder gene effect. PMID:20019388

  6. The A1555G Mutation in the 12S rRNA Gene of Human mtDNA: Recurrent Origins and Founder Events in Families Affected by Sensorineural Deafness

    PubMed Central

    Torroni, Antonio; Cruciani, Fulvio; Rengo, Chiara; Sellitto, Daniele; López-Bigas, Núria; Rabionet, Raquel; Govea, Nancy; López de Munain, Adolfo; Sarduy, Maritza; Romero, Lourdes; Villamar, Manuela; del Castillo, Ignacio; Moreno, Felipe; Estivill, Xavier; Scozzari, Rosaria

    1999-01-01

    Summary The mtDNA variation of 50 Spanish and 4 Cuban families affected by nonsyndromic sensorineural deafness due to the A1555G mutation in the 12S rRNA gene was studied by high-resolution RFLP analysis and sequencing of the control region. Phylogenetic analyses of haplotypes and detailed survey of population controls revealed that the A1555G mutation can be attributed to ⩾30 independent mutational events among the 50 Spanish families and that it occurs on mtDNA haplogroups that are common in all European populations. This indicates that the relatively high detection rate of this mutation in Spain is not due to sampling biases or to a single major founder event. Moreover, the distribution of these mutational events on different haplogroups is compatible with a random occurrence of the A1555G mutation and tends to support the conclusion that mtDNA backgrounds do not play a significant role in the expression of the mutation. Overall, these findings appear to indicate that the rare detection of this mutation in other populations is most likely due to inadequacy in patient ascertainment and molecular screening. This probable lack of identification of the A1555G mutation in subjects affected by sensorineural hearing loss implies that their maternally related relatives are not benefiting from presymptomatic detection and information concerning their increased risk of ototoxicity due to aminoglycoside treatments. PMID:10521300

  7. Fine-Mapping the Wheat Snn1 Locus Conferring Sensitivity to the Parastagonospora nodorum Necrotrophic Effector SnTox1 Using an Eight Founder Multiparent Advanced Generation Inter-Cross Population

    PubMed Central

    Cockram, James; Scuderi, Alice; Barber, Toby; Furuki, Eiko; Gardner, Keith A.; Gosman, Nick; Kowalczyk, Radoslaw; Phan, Huyen P.; Rose, Gemma A.; Tan, Kar-Chun; Oliver, Richard P.; Mackay, Ian J.

    2015-01-01

    The necrotrophic fungus Parastagonospora nodorum is an important pathogen of one of the world’s most economically important cereal crops, wheat (Triticum aestivum L.). P. nodorum produces necrotrophic protein effectors that mediate host cell death, providing nutrients for continuation of the infection process. The recent discovery of pathogen effectors has revolutionized disease resistance breeding for necrotrophic diseases in crop species, allowing often complex genetic resistance mechanisms to be broken down into constituent parts. To date, three effectors have been identified in P. nodorum. Here we use the effector, SnTox1, to screen 642 progeny from an eight-parent multiparent advanced generation inter-cross (i.e., MAGIC) population, genotyped with a 90,000-feature single-nucleotide polymorphism array. The MAGIC founders showed a range of sensitivity to SnTox1, with transgressive segregation evident in the progeny. SnTox1 sensitivity showed high heritability, with quantitative trait locus analyses fine-mapping the Snn1 locus to the short arm of chromosome 1B. In addition, a previously undescribed SnTox1 sensitivity locus was identified on the long arm of chromosome 5A, termed here QSnn.niab-5A.1. The peak single-nucleotide polymorphism for the Snn1 locus was converted to the KASP genotyping platform, providing breeders and researchers a simple and cheap diagnostic marker for allelic state at Snn1. PMID:26416667

  8. BRCA1 5272-1G>A and BRCA2 5374delTATG are founder mutations of high relevance for genetic counselling in breast/ovarian cancer families of Spanish origin.

    PubMed

    Infante, M; Durán, M; Acedo, A; Pérez-Cabornero, L; Sanz, D J; García-González, M; Beristain, E; Esteban-Cardeñosa, E; de la Hoya, M; Teulé, A; Vega, A; Tejada, M-I; Lastra, E; Miner, C; Velasco, E A

    2010-01-01

    The distribution of BRCA1 and BRCA2 germ line mutations in breast/ovarian cancer families varies among different populations, which typically present a wide spectrum of unique mutations. Splicing mutation 5272-1G>A of BRCA1 and frameshift mutation 5374delTATG of BRCA2 are highly prevalent mutations in Castilla-León (Spain), accounting for 18.4% and 13.6% of BRCA1 and BRCA2 positive families, respectively. To test the presence of founder effects, 9 Spanish 5272-1G>A and 13 5374delTATG families were genotyped with polymorphic markers linked to BRCA1 or BRCA2. All the 5272-1G>A families shared a common haplotype in eight markers (1.1 Mb region) and the mutation age was estimated in 15 generations (approximately 380 years). A conserved haplotype associated to 5374delTATG was observed in four markers (0.82 Mb). The mutation occurred approximately 48 generations ago (approximately 1200 years). Each mutation likely arose from a common ancestor that could be traced to a small area of Castilla-León and expanded to other Spanish regions. They can have a significant impact on the clinical management of asymptomatic carriers as well as on the genetic screening strategy to be followed in populations with Spanish ancestries. PMID:19912264

  9. Grace Burnham McDonald, founder of the Workers' Health Bureau: "you have to see it in the context of organized labor's right to survive and to represent its members".

    PubMed

    Gluck, Sherna Berger; Dunn, Mary Lee; Slatin, Craig

    2014-11-01

    Grace Burnham McDonald (born in 1889) was a founder of the Workers Health Bureau in New York City in 1921. She started the Bureau after her experience with the Joint Board of Sanitary Control. The Bureau assessed workplace health and safety risks, educated labor unions about these issues, and advocated for laws to ensure the highest degree of workplace protection. Her Bureau colleagues were Harriet Silverman and Charlotte Todes (Stern). Burnham McDonald supported the Bureau with part of her 1923 inheritance from her first husband. After years of effective work, the Workers' Health Bureau shut down in 1929, largely as a result of diminished support from the unions, whose focus had shifted to purely economic issues, and the dissociation of the AFL from the Bureau. In later life, Burnham McDonald moved to California, where she became involved in some of the same causes, especially as they affected agricultural laborers. An interview with Charlotte Todes Stern follows and appears on page 337 of this issue. PMID:25261026

  10. High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme.

    PubMed

    Apellániz-Ruiz, M; Inglada-Pérez, L; Naranjo, M E G; Sánchez, L; Mancikova, V; Currás-Freixes, M; de Cubas, A A; Comino-Méndez, I; Triki, S; Rebai, A; Rasool, M; Moya, G; Grazina, M; Opocher, G; Cascón, A; Taboada-Echalar, P; Ingelman-Sundberg, M; Carracedo, A; Robledo, M; Llerena, A; Rodríguez-Antona, C

    2015-06-01

    Cytochrome P450 3A4 (CYP3A4) is a key drug-metabolizing enzyme. Loss-of-function variants have been reported as rare events, and the first demonstration of a CYP3A4 protein lacking functional activity is caused by CYP3A4*20 allele. Here we characterized the world distribution and origin of CYP3A4*20 mutation. CYP3A4*20 was determined in more than 4000 individuals representing different populations, and haplotype analysis was performed using CYP3A polymorphisms and microsatellite markers. CYP3A4*20 allele was present in 1.2% of the Spanish population (up to 3.8% in specific regions), and all CYP3A4*20 carriers had a common haplotype. This is compatible with a Spanish founder effect and classifies CYP3A4 as a polymorphic enzyme. This constitutes the first description of a CYP3A4 loss-of-function variant with high frequency in a population. CYP3A4*20 results together with the key role of CYP3A4 in drug metabolism support screening for rare CYP3A4 functional alleles among subjects with adverse drug events in certain populations. PMID:25348618

  11. Metabolomic Assessment of Key Maize Resources: GC-MS and NMR Profiling of Grain from B73 Hybrids of the Nested Association Mapping (NAM) Founders and of Geographically Diverse Landraces.

    PubMed

    Venkatesh, Tyamagondlu V; Chassy, Alexander W; Fiehn, Oliver; Flint-Garcia, Sherry; Zeng, Qin; Skogerson, Kirsten; Harrigan, George G

    2016-03-16

    The present study expands metabolomic assessments of maize beyond commercial lines to include two sets of hybrids used extensively in the scientific community. One set included hybrids derived from the nested association mapping (NAM) founder lines, a collection of 25 inbreds selected on the basis of genetic diversity and used to investigate the genetic basis of complex plant traits. A second set included 24 hybrids derived from a collection of landraces representative of native diversity from North and South America that may serve as a source of new alleles for improving modern maize hybrids. Metabolomic analysis of grain harvested from these hybrids utilized gas chromatography-time-of-flight mass spectrometry (GC-TOF-MS) and (1)H nuclear magnetic resonance spectroscopy ((1)H NMR) techniques. Results highlighted extensive metabolomic variation in grain from both hybrid sets, but also demonstrated that, within each hybrid set, subpopulations could be differentiated in a pattern consistent with the known genetic and compositional variation of these lines. Correlation analysis did not indicate a strong association of the metabolomic data with grain nutrient composition, although some metabolites did show moderately strong correlations with agronomic features such as plant and ear height. Overall, this study provides insights into the extensive metabolomic diversity associated with conventional maize germplasm. PMID:26923484

  12. Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) Founder Mutation: Clues from Haplotyping of Short Tandem Repeats on Chromosome 17p

    PubMed Central

    Paskulin, Diego Davila; Giacomazzi, Juliana; Achatz, Maria Isabel; Costa, Sandra; Reis, Rui Manoel; Hainaut, Pierre; dos Santos, Sidney Emanuel Batista; Ashton-Prolla, Patricia

    2015-01-01

    Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil. This mutation is associated with partially penetrant LFS traits and is found in the germline of patients with early cancers of the LFS spectrum unselected for familial history. To characterize the extended haplotypes carrying the mutation, we have genotyped 9 short tandem repeats on chromosome 17p in 12 trios of Brazilian p.Arg337His carriers. Results confirm that all share a common ancestor haplotype of Caucasian/Portuguese-Iberic origin, distant in about 72–84 generations (2000 years assuming a 25 years intergenerational distance) and thus pre-dating European migration to Brazil. So far, the founder p.Arg337His haplotype has not been detected outside Brazil, with the exception of two residents of Portugal, one of them of Brazilian origin. On the other hand, increased meiotic recombination in p.Arg337His carriers may account for higher than expected haplotype diversity. Further studies comparing haplotypes in populations of Brazil and of other areas of Portuguese migration are needed to understand the historical context of this mutation in Brazil. PMID:26618902

  13. Contribution of the PALB2 c.2323C>T [p.Q775X] Founder mutation in well-defined breast and/or ovarian cancer families and unselected ovarian cancer cases of French Canadian descent

    PubMed Central

    2013-01-01

    Background The PALB2 c.2323C>T [p.Q775X] mutation has been reported in at least three breast cancer families and breast cancer cases of French Canadian descent and this has been attributed to common ancestors. The number of mutation-positive cases reported varied based on criteria of ascertainment of index cases tested. Although inherited PALB2 mutations are associated with increased risks of developing breast cancer, risk to ovarian cancer has not been fully explored in this demographically unique population. Methods We screened the PALB2 p.Q775X variant in 71 families with at least three cases of breast cancer (n=48) or breast and ovarian cancers (n=23) that have previously been found negative for at least the most common BRCA1 and BRCA2 mutations reported in the French Canadian population and in 491 women of French Canadian descent who had invasive ovarian cancer and/or low malignant potential tumors of the major histopathological subtypes. Results We identified a PALB2 p.Q775X carrier in a breast cancer family, who had invasive ductal breast carcinomas at 39 and 42 years of age. We also identified a PALB2 p.Q775X carrier who had papillary serous ovarian cystadenocarcinoma at age 58 among the 238 serous subtype ovarian cancer cases investigated, who also had breast cancer at age 52. Conclusion Our findings, taken together with previous reports, support adding PALB2 c.2323C>T p.Q775X to the list of cancer susceptibility genes for which founder mutations have been identified in the French Canadian population. PMID:23302520

  14. Robert Boyle: The Founder of Modern Chemistry

    NASA Astrophysics Data System (ADS)

    Williams, Kathryn R.

    2009-02-01

    When I learned that the 2009 Earth Day features "air", I started thinking about a suitable way to link the topic to past JCE issues. No small task, considering that I had already covered oxygen and nitrogen in the 2003 and 2005 Earth Day issues. So much for chemical composition. So, I turned to physical properties—the gas laws—that could equally be called the "air laws", since "air" was a generic word for a gas in the centuries when the laws were formulated. For Earth Day 2009, I focus on Robert Boyle, who discovered the first of the gas laws. In addition to at least 20 papers describing Boyle's Law demonstrations and experiments, The Honorable Robert Boyle (1627-1691) is the subject of five papers in JCE .

  15. Founder lines for improved citrus biotechnology

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This article discusses the research needed to develop the RMCE strategy and molecular assays for site-specific recombinases as tools for genome manipulation. Explanation of genetic engineering used to generate transgenic citrus plants to exhibit a novel phenotype, but not to contain the recombinase...

  16. Founders of fish culture - European origins

    USGS Publications Warehouse

    Fish, F.F.

    1936-01-01

    Just where true fish culture appeared in history depends entirely upon what one considers fish culture to be. If the transportation of fishes from regions of plenty to those of few is to be regarded as fish culture - as it is by some even today - then this story should start in remotest antiquity and deal with an amazing series of failures. However, fish culture to be classed as a science must include far more than mere transportation, it must include a deliberate effort on the part of man to master a technique of fish raising which will yield results far superior to Nature's. Accordingly, the wheel of history must be spun forward to the fifteenth century, A. D., when man first conceived the idea that with care and exactitude, he could improve upon Nature. The fish cultural efforts of the Chinese, the Egyptians, the Greeks, and the Romans may be skipped over in a hurry, for they represented little more than the transportation and rearing of wild fish. With the renaissance of modern civilization in Europe came the birth of scientific fish culture.

  17. Questioning the Founders--and Ourselves

    ERIC Educational Resources Information Center

    Lindsay, Thomas K.

    2012-01-01

    The question of the relation between liberal education and political liberty, perennially important, is driven for this forum by the Obama administration's endorsement of "A Crucible Moment: College Learning & Democracy's Future," according to which the chief ends of postsecondary civic education ought to include the promotion of sweeping…

  18. Role of arc magmatism and lower crustal foundering in controlling elevation history of the Nevadaplano and Colorado Plateau: A case study of pyroxenitic lower crust from central Arizona, USA

    NASA Astrophysics Data System (ADS)

    Erdman, Monica E.; Lee, Cin-Ty A.; Levander, Alan; Jiang, Hehe

    2016-04-01

    Garnet-pyroxenite xenoliths from a 25 Ma volcano on the southern edge of the Colorado Plateau in central Arizona (USA) are shown here to have crystallized as deep-seated cumulates from hydrous arc magmas, requiring the generation of a large complement of felsic magmas. U-Pb dating of primary titanite grains indicates that crystallization probably occurred around 60 Ma. These observations suggest that voluminous arc magmatism reached as far inland as the edge of the Colorado Plateau during the Laramide orogeny. Here, we employ a combination of petrology, petrophysics, and seismic imaging to show that the formation and subsequent removal of a thick, dense, cumulate root beneath the ancient North American Nevadaplano modified the buoyancy of the orogenic plateau, possibly resulting in two uplift events. A late Cretaceous-early Tertiary uplift event should have occurred in conjunction with thickening of the crust by felsic magmatism. Additional uplift is predicted if the pyroxenite root later foundered, but such uplift must have occurred after ∼25 Ma, the age of the xenolith host. We show that seismic velocity anomalies and seismic structures in the central part of the Colorado Plateau could represent pyroxenitic layers that still reside there. However, under the southern and western margins of the Colorado Plateau, the seismic signatures of a pyroxenite root are missing, despite xenolith records and geochemical evidence for their existence prior to 25 Ma. We suggest that these particular regions have undergone recent removal of the pyroxenite root, leading to late uplift of the plateau. In summary, our observations suggest that the Nevadaplano, west of the Colorado Plateau and now represented by the Basin and Range province, was underlain by high elevations in the late Cretaceous through early Tertiary due to magmatic thickening. This may have facilitated an east-directed drainage pattern at this time. Subsequent collapse of the Nevadaplano, culminating in Basin and

  19. Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost

    PubMed Central

    Hulot, Sandrine L.; Korber, Bette; Giorgi, Elena E.; Vandergrift, Nathan; Saunders, Kevin O.; Balachandran, Harikrishnan; Mach, Linh V.; Lifton, Michelle A.; Pantaleo, Giuseppe; Tartaglia, Jim; Phogat, Sanjay; Jacobs, Bertram; Kibler, Karen; Perdiguero, Beatriz; Gomez, Carmen E.; Esteban, Mariano; Rosati, Margherita; Felber, Barbara K.; Pavlakis, George N.; Parks, Robert; Lloyd, Krissey; Sutherland, Laura; Scearce, Richard; Letvin, Norman L.; Seaman, Michael S.; Alam, S. Munir; Montefiori, David; Liao, Hua-Xin; Haynes, Barton F.

    2015-01-01

    ABSTRACT An effective human immunodeficiency virus type 1 (HIV-1) vaccine must induce protective antibody responses, as well as CD4+ and CD8+ T cell responses, that can be effective despite extraordinary diversity of HIV-1. The consensus and mosaic immunogens are complete but artificial proteins, computationally designed to elicit immune responses with improved cross-reactive breadth, to attempt to overcome the challenge of global HIV diversity. In this study, we have compared the immunogenicity of a transmitted-founder (T/F) B clade Env (B.1059), a global group M consensus Env (Con-S), and a global trivalent mosaic Env protein in rhesus macaques. These antigens were delivered using a DNA prime-recombinant NYVAC (rNYVAC) vector and Env protein boost vaccination strategy. While Con-S Env was a single sequence, mosaic immunogens were a set of three Envs optimized to include the most common forms of potential T cell epitopes. Both Con-S and mosaic sequences retained common amino acids encompassed by both antibody and T cell epitopes and were central to globally circulating strains. Mosaics and Con-S Envs expressed as full-length proteins bound well to a number of neutralizing antibodies with discontinuous epitopes. Also, both consensus and mosaic immunogens induced significantly higher gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses than B.1059 immunogen. Immunization with these proteins, particularly Con-S, also induced significantly higher neutralizing antibodies to viruses than B.1059 Env, primarily to tier 1 viruses. Both Con-S and mosaics stimulated more potent CD8-T cell responses against heterologous Envs than did B.1059. Both antibody and cellular data from this study strengthen the concept of using in silico-designed centralized immunogens for global HIV-1 vaccine development strategies. IMPORTANCE There is an increasing appreciation for the importance of vaccine-induced anti-Env antibody responses for preventing HIV-1

  20. Transmitted/Founder and Chronic Subtype C HIV-1 Use CD4 and CCR5 Receptors with Equal Efficiency and Are Not Inhibited by Blocking the Integrin α4β7

    PubMed Central

    Banks, Lauren B.; Iyer, Shilpa S.; Pfaff, Jennifer M.; Salazar-Gonzalez, Jesus F.; Salazar, Maria G.; Decker, Julie M.; Parrish, Erica H.; Berg, Anna; Hopper, Jennifer; Hora, Bhavna; Kumar, Amit; Mahlokozera, Tatenda; Yuan, Sally; Coleman, Charl; Vermeulen, Marion; Ding, Haitao; Ochsenbauer, Christina; Tilton, John C.; Permar, Sallie R.; Kappes, John C.; Betts, Michael R.; Busch, Michael P.; Gao, Feng; Montefiori, David; Haynes, Barton F.; Shaw, George M.; Hahn, Beatrice H.; Doms, Robert W.

    2012-01-01

    Sexual transmission of human immunodeficiency virus type 1 (HIV-1) most often results from productive infection by a single transmitted/founder (T/F) virus, indicating a stringent mucosal bottleneck. Understanding the viral traits that overcome this bottleneck could have important implications for HIV-1 vaccine design and other prevention strategies. Most T/F viruses use CCR5 to infect target cells and some encode envelope glycoproteins (Envs) that contain fewer potential N-linked glycosylation sites and shorter V1/V2 variable loops than Envs from chronic viruses. Moreover, it has been reported that the gp120 subunits of certain transmitted Envs bind to the gut-homing integrin α4β7, possibly enhancing virus entry and cell-to-cell spread. Here we sought to determine whether subtype C T/F viruses, which are responsible for the majority of new HIV-1 infections worldwide, share biological properties that increase their transmission fitness, including preferential α4β7 engagement. Using single genome amplification, we generated panels of both T/F (n = 20) and chronic (n = 20) Env constructs as well as full-length T/F (n = 6) and chronic (n = 4) infectious molecular clones (IMCs). We found that T/F and chronic control Envs were indistinguishable in the efficiency with which they used CD4 and CCR5. Both groups of Envs also exhibited the same CD4+ T cell subset tropism and showed similar sensitivity to neutralization by CD4 binding site (CD4bs) antibodies. Finally, saturating concentrations of anti-α4β7 antibodies failed to inhibit infection and replication of T/F as well as chronic control viruses, although the growth of the tissue culture-adapted strain SF162 was modestly impaired. These results indicate that the population bottleneck associated with mucosal HIV-1 acquisition is not due to the selection of T/F viruses that use α4β7, CD4 or CCR5 more efficiently. PMID:22693444

  1. Distal Limits and Composition of a Late Ordovician (Mohawkian) Biotite-Bearing Volcanic ash, Foreland Carbonate Platform (Verulam Formation), Ottawa Embayment: Helping to Define Magmatic Change in Volcanism Following Later Platform Foundering

    NASA Astrophysics Data System (ADS)

    Al-Delami, M.; Dix, G. R.

    2009-05-01

    burial temperatures of 130oC, in keeping with burial temperature estimates according to conodont alteration indices (CAI = 3) for the host carbonate platform succession. The MgO and FeO % of biotites from these beds plot within the same field as the slightly older Millbrig and Deike bentonites that also represent ash deposition within shallow-water carbonate platform environments from widespread Late Ordovician eruptions that occurred along the foreland basin margin. Collectively, these compositions are higher in FeO and lower in MgO % values compared those associated with a bentonite within the overlying Taconic foreland shale succession of the Ottawa Embayment, and bentonites in Lower Silurian successions of western Europe. This contrast strengthens a previous hypothesis (Sharma et al., 2005) that there was significant change in magmatic composition along the Taconic arc following or coincident with foundering of the foreland carbonate platform.

  2. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women

    SciTech Connect

    Abeliovich, D.; Lerer, I.; Weinberg, N.

    1997-03-01

    The mutations 185delAG, 188del11, and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene were analyzed in 199 Ashkenazi and 44 non-Ashkenazi Jewish unrelated patients with breast and/or ovarian cancer. Of the Jewish Ashkenazi women with ovarian cancer, 62% (13/21) had one of the target mutations, as did 30% (13/43) of women with breast cancer alone diagnosed before the age 40 years and 10% (15/141) of those with breast cancer diagnosed after the age 40 years. Age at ovarian cancer diagnosis was not associated with carrier status. Of 99 Ashkenazi patients with no family history of breast and/or ovarian cancer, 10% carried one of the mutations; in two of them the mutation was proved to be paternally transmitted. One non-Ashkenazi Jewish ovarian cancer patient from Iraq carried the 185delAG mutation. Individual mutation frequencies among breast cancer Ashkenazi patients were 6.7% for 185delAG, 2.2% for 5382insC, and 4.5% for 6174delT, among ovarian cancer patients; 185delAG and 6174delT were about equally common (33% and 29%, respectively), but no ovarian cancer patient carried the 5382insC. More mutations responsible for inherited breast and ovarian cancer probably remain to be found in this population, since 79% of high-incidence breast cancer families and 35% of high-incidence breast/ovarian cancer families had none of the three known founder mutations. 25 refs., 3 figs., 6 tabs.

  3. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women.

    PubMed Central

    Abeliovich, D; Kaduri, L; Lerer, I; Weinberg, N; Amir, G; Sagi, M; Zlotogora, J; Heching, N; Peretz, T

    1997-01-01

    The mutations 185delAG, 188del11, and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene were analyzed in 199 Ashkenazi and 44 non-Ashkenazi Jewish unrelated patients with breast and/or ovarian cancer. Of the Jewish Ashkenazi women with ovarian cancer, 62% (13/21) had one of the target mutations, as did 30% (13/43) of women with breast cancer alone diagnosed before the age 40 years and 10% (15/141) of those with breast cancer diagnosed after the age 40 years. Age at ovarian cancer diagnosis was not associated with carrier status. Of 99 Ashkenazi patients with no family history of breast and/or ovarian cancer, 10% carried one of the mutations; in two of them the mutation was proved to be paternally transmitted. One non-Ashkenazi Jewish ovarian cancer patient from Iraq carried the 185delAG mutation. Individual mutation frequencies among breast cancer Ashkenazi patients were 6.7% for 185delAG, 2.2% for 5382insC, and 4.5% for 6174delT, among ovarian cancer patients; 185delAG and 6174delT were about equally common (33% and 29%, respectively), but no ovarian cancer patient carried the 5382insC. More mutations responsible for inherited breast and ovarian cancer probably remain to be found in this population, since 79% of high-incidence breast cancer families and 35% of high-incidence breast/ovarian cancer families had none of the three known founder mutations. Images Figure 2 Figure 3 PMID:9042909

  4. [Charles Robert Darwin: the great founder of scientific evolutionism].

    PubMed

    Liang, Qian-Jin; Bin, Jie; Zhang, Gen-Fa

    2009-12-01

    Today, we celebrated 200 years since Charles Darwin, one of the world's most creative and influential thinkers, was born. And there happens to be the 150th anniversary of the publication of his famous book, On the Origin of Species. It is verified that On the Origin of Species is an immortal classic book and is still guiding the study of anagenesis in life science as the development of natural science from then on, and even though most of the ideas in the book are well-known at the present age. In the article, we recall the brilliance and predomination life of Darwin, a great sage with rich scientific achievements, review briefly the novel discoveries and theories after him in the field, and then elucidate the focal points and perspectiveas in near future study of evolution. PMID:20042383

  5. Far above rubies: the founders of Every Child By Two.

    PubMed

    Wiederhorn, N

    1992-01-01

    The Every Child By Two Campaign was formed by Rosalynn Carter and Betty Bumpers, spouses of prominent elected officials, in response to the rapid increase in measles cases in the United States in 1990. They have sought to create a network of community leaders that will act to get children immunized now and will influence legislation to ensure that children under two will be fully immunized in the future. PMID:1408425

  6. Rejuvenating a foundering institutional review board: one institution's story.

    PubMed

    De Ville, Kenneth; Hassler, Gregory; Lewis, Michael J

    2007-01-01

    This report recounts one institution's experience in the fundamental reorganization of its institutional review board (IRB). With an appropriate approach, organizational structure, and ethos, the goals of research participant safety, regulatory compliance, and efficiency are not in conflict but, rather, mutually reinforcing. These important goals were realized because all aspects of the IRB reorganization were guided by and measured against five related principles: (1) expertise, (2) service, (3) credibility, (4) efficiency, and (5) accountability. This medium-sized academic IRB was successfully reorganized to increase the scrutiny of protection of human subjects and to promote efficiency and investigator services. On average, the office returned expedited submissions to investigators with approvals or queries within two working days of submission. On submissions requiring full committee review, letters and faxes were issued to investigators within 48 hours of committee meetings. This turnaround time (combined with a nine-day premeeting submission requirement) meant that investigators who had submitted new studies for full committee review received an approval, request for modifications, queries for more information, or disapproval within 11 days from the reorganized IRB. In contrast, an Office of the Inspector General study noted that IRBs in academic medical centers typically report decisions within an average of 37 days. The reforms included mechanical and operational changes within office procedure, a robust educational program for committee members, and a revamped IRB office staff that decreased the total number of office employees from five to four but that increased educational levels and skills of the staff members. PMID:17198283

  7. The Founders of the XXth Century Stellar Photometry in Russia

    NASA Astrophysics Data System (ADS)

    Pustylnik, I.; Mironov, A.

    Our contribution is dedicated to two ``godfathers'' of astrophotometry in Russia - Vitold Karlovich Ceraski (1849-1925) and Vladimir Borisovich Nikonov (1905-1987). We discuss their scientific legacy and its impact upon the formation of the school of stellar photometry in Russia and the USSR. The graduate of Moscow University in 1871 V. Ceraski started his scientific career in the University astronomical observatory. Already at the dawn of XXth century he was universally regarded as an indisputable authority in Russian astrophotometry. Ceraski introduced essential improvements into the K.-F. Zöllner's visual polarimetric photometer. With its aid he measured in 1903-1905 the stellar magnitude of the Sun with an accuracy close to its modern value (within a 5 % margin) by carefully comparing the brightness of Venus with that of the speck of the solar light reflected from the convex glass surface (during the day) and by comparing the brightness of Venus with that of the brightest stars (in the night). V. Nikonov, the graduate of Leningrad University, in 1925 embarked upon scientific investigations in the local Astronomical Institute. During these years the 13 inch reflector has been installed by Leningrad astronomers at the mountain Kanobili (Abastumani observatory, Georgia). In 1937 Nikonov constructed the first in the USSR photoelectric photometer. Experiments with it indicated that the attainable precision for 4.5m stars amounted to 0.003m. It was obvious for Nikonov that with such a precision one should exercise extreme care in reduction of stellar magnitudes beyond the earth's upper atmosphere. In 1944 he elaborated a method to account for atmospheric extinction which is now universally known as Nikonov's method. Its underlying idea lies in the observations of all non-variable stars available in the program for different air masses.

  8. Grain founder in a male camel (Camelus dromedarius)

    PubMed Central

    Sharma, Sunanda

    2006-01-01

    A rare case of laminitis was recorded in an adult camel that was kept in confinement without giving any exercise and fed daily with considerable quantity of pearl millet grains (Pennisetum typhoideus) for more than five months. PMID:16434859

  9. Lessons Learned: The Edison Project Founder's Musings on American Schooling.

    ERIC Educational Resources Information Center

    Whittle, Christopher

    1997-01-01

    The entrepreneur behind the Edison Project and Channel One shares his observations about the unfairness of public school critics, the "tyranny" of operational demands, and the promise of national school companies for underemployed teachers and research and development ventures. Praising public schools for being receptive to new concepts, the…

  10. Wolfgang Schott (1905-1989): the founder of quantitative paleoceanography

    NASA Astrophysics Data System (ADS)

    Dullo, Wolf-Christian; Pfaffl, Fritz A.

    2016-06-01

    Wolfgang Schott is the pioneer in paleoceanography and has established this research field within marine geology. His papers from the first half of the twentieth century are all published in German; therefore, the most inspiring results are given here as original quotes in English, since they paved the ground for all scientific discussions on climate stratigraphy, past ocean currents, and glacial interglacial cycles.